Daily Papers

We extend molecular bootstrap embedding to make it appropriate for implementation on a quantum computer. This enables solution of the electronic structure problem of a large molecule as an optimization problem for a composite Lagrangian governing fragments of the total system, in such a way that fragment solutions can harness the capabilities of quantum computers. By employing state-of-art quantum subroutines including the quantum SWAP test and quantum amplitude amplification, we show how a quadratic speedup can be obtained over the classical algorithm, in principle. Utilization of quantum computation also allows the algorithm to match -- at little additional computational cost -- full density matrices at fragment boundaries, instead of being limited to 1-RDMs. Current quantum computers are small, but quantum bootstrap embedding provides a potentially generalizable strategy for harnessing such small machines through quantum fragment matching.

Accurate blind docking has the potential to lead to new biological breakthroughs, but for this promise to be realized, docking methods must generalize well across the proteome. Existing benchmarks, however, fail to rigorously assess generalizability. Therefore, we develop DockGen, a new benchmark based on the ligand-binding domains of proteins, and we show that existing machine learning-based docking models have very weak generalization abilities. We carefully analyze the scaling laws of ML-based docking and show that, by scaling data and model size, as well as integrating synthetic data strategies, we are able to significantly increase the generalization capacity and set new state-of-the-art performance across benchmarks. Further, we propose Confidence Bootstrapping, a new training paradigm that solely relies on the interaction between diffusion and confidence models and exploits the multi-resolution generation process of diffusion models. We demonstrate that Confidence Bootstrapping significantly improves the ability of ML-based docking methods to dock to unseen protein classes, edging closer to accurate and generalizable blind docking methods.

Molecular Representation Learning (MRL) has proven impactful in numerous biochemical applications such as drug discovery and enzyme design. While Graph Neural Networks (GNNs) are effective at learning molecular representations from a 2D molecular graph or a single 3D structure, existing works often overlook the flexible nature of molecules, which continuously interconvert across conformations via chemical bond rotations and minor vibrational perturbations. To better account for molecular flexibility, some recent works formulate MRL as an ensemble learning problem, focusing on explicitly learning from a set of conformer structures. However, most of these studies have limited datasets, tasks, and models. In this work, we introduce the first MoleculAR Conformer Ensemble Learning (MARCEL) benchmark to thoroughly evaluate the potential of learning on conformer ensembles and suggest promising research directions. MARCEL includes four datasets covering diverse molecule- and reaction-level properties of chemically diverse molecules including organocatalysts and transition-metal catalysts, extending beyond the scope of common GNN benchmarks that are confined to drug-like molecules. In addition, we conduct a comprehensive empirical study, which benchmarks representative 1D, 2D, and 3D molecular representation learning models, along with two strategies that explicitly incorporate conformer ensembles into 3D MRL models. Our findings reveal that direct learning from an accessible conformer space can improve performance on a variety of tasks and models.

We seek to automate the design of molecules based on specific chemical properties. In computational terms, this task involves continuous embedding and generation of molecular graphs. Our primary contribution is the direct realization of molecular graphs, a task previously approached by generating linear SMILES strings instead of graphs. Our junction tree variational autoencoder generates molecular graphs in two phases, by first generating a tree-structured scaffold over chemical substructures, and then combining them into a molecule with a graph message passing network. This approach allows us to incrementally expand molecules while maintaining chemical validity at every step. We evaluate our model on multiple tasks ranging from molecular generation to optimization. Across these tasks, our model outperforms previous state-of-the-art baselines by a significant margin.

Understanding molecules is key to understanding organisms and driving advances in drug discovery, requiring interdisciplinary knowledge across chemistry and biology. Although large molecular language models have achieved notable success in interpreting molecular structures, their instruction datasets are limited to the specific knowledge from task-oriented datasets and do not fully cover the fundamental characteristics of molecules, hindering their abilities as general-purpose molecular assistants. To address this issue, we propose Mol-LLaMA, a large molecular language model that grasps the general knowledge centered on molecules via multi-modal instruction tuning. To this end, we design key data types that encompass the fundamental features of molecules, incorporating essential knowledge from molecular structures. In addition, to improve understanding of molecular features, we introduce a module that integrates complementary information from different molecular encoders, leveraging the distinct advantages of different molecular representations. Our experimental results demonstrate that Mol-LLaMA is capable of comprehending the general features of molecules and generating relevant responses to users' queries with detailed explanations, implying its potential as a general-purpose assistant for molecular analysis.

The bootstrap is a popular data-driven method to quantify statistical uncertainty, but for modern high-dimensional problems, it could suffer from huge computational costs due to the need to repeatedly generate resamples and refit models. We study the use of bootstraps in high-dimensional environments with a small number of resamples. In particular, we show that with a recent "cheap" bootstrap perspective, using a number of resamples as small as one could attain valid coverage even when the dimension grows closely with the sample size, thus strongly supporting the implementability of the bootstrap for large-scale problems. We validate our theoretical results and compare the performance of our approach with other benchmarks via a range of experiments.

The recent success of large foundation models in artificial intelligence has prompted the emergence of chemical pre-trained models. Despite the growing interest in large molecular pre-trained models that provide informative representations for downstream tasks, attempts for multimodal pre-training approaches on the molecule domain were limited. To address this, we present a novel multimodal molecular pre-trained model that incorporates the modalities of structure and biochemical properties, drawing inspiration from recent advances in multimodal learning techniques. Our proposed model pipeline of data handling and training objectives aligns the structure/property features in a common embedding space, which enables the model to regard bidirectional information between the molecules' structure and properties. These contributions emerge synergistic knowledge, allowing us to tackle both multimodal and unimodal downstream tasks through a single model. Through extensive experiments, we demonstrate that our model shows remarkable capabilities in solving various meaningful chemical challenges, including conditional molecule generation, property prediction, molecule classification, and reaction prediction.

The integration of biomolecular modeling with natural language (BL) has emerged as a promising interdisciplinary area at the intersection of artificial intelligence, chemistry and biology. This approach leverages the rich, multifaceted descriptions of biomolecules contained within textual data sources to enhance our fundamental understanding and enable downstream computational tasks such as biomolecule property prediction. The fusion of the nuanced narratives expressed through natural language with the structural and functional specifics of biomolecules described via various molecular modeling techniques opens new avenues for comprehensively representing and analyzing biomolecules. By incorporating the contextual language data that surrounds biomolecules into their modeling, BL aims to capture a holistic view encompassing both the symbolic qualities conveyed through language as well as quantitative structural characteristics. In this review, we provide an extensive analysis of recent advancements achieved through cross modeling of biomolecules and natural language. (1) We begin by outlining the technical representations of biomolecules employed, including sequences, 2D graphs, and 3D structures. (2) We then examine in depth the rationale and key objectives underlying effective multi-modal integration of language and molecular data sources. (3) We subsequently survey the practical applications enabled to date in this developing research area. (4) We also compile and summarize the available resources and datasets to facilitate future work. (5) Looking ahead, we identify several promising research directions worthy of further exploration and investment to continue advancing the field. The related resources and contents are updating in https://github.com/QizhiPei/Awesome-Biomolecule-Language-Cross-Modeling.

Recently, pre-trained foundation models have enabled significant advancements in multiple fields. In molecular machine learning, however, where datasets are often hand-curated, and hence typically small, the lack of datasets with labeled features, and codebases to manage those datasets, has hindered the development of foundation models. In this work, we present seven novel datasets categorized by size into three distinct categories: ToyMix, LargeMix and UltraLarge. These datasets push the boundaries in both the scale and the diversity of supervised labels for molecular learning. They cover nearly 100 million molecules and over 3000 sparsely defined tasks, totaling more than 13 billion individual labels of both quantum and biological nature. In comparison, our datasets contain 300 times more data points than the widely used OGB-LSC PCQM4Mv2 dataset, and 13 times more than the quantum-only QM1B dataset. In addition, to support the development of foundational models based on our proposed datasets, we present the Graphium graph machine learning library which simplifies the process of building and training molecular machine learning models for multi-task and multi-level molecular datasets. Finally, we present a range of baseline results as a starting point of multi-task and multi-level training on these datasets. Empirically, we observe that performance on low-resource biological datasets show improvement by also training on large amounts of quantum data. This indicates that there may be potential in multi-task and multi-level training of a foundation model and fine-tuning it to resource-constrained downstream tasks.

Molecular machine learning has been maturing rapidly over the last few years. Improved methods and the presence of larger datasets have enabled machine learning algorithms to make increasingly accurate predictions about molecular properties. However, algorithmic progress has been limited due to the lack of a standard benchmark to compare the efficacy of proposed methods; most new algorithms are benchmarked on different datasets making it challenging to gauge the quality of proposed methods. This work introduces MoleculeNet, a large scale benchmark for molecular machine learning. MoleculeNet curates multiple public datasets, establishes metrics for evaluation, and offers high quality open-source implementations of multiple previously proposed molecular featurization and learning algorithms (released as part of the DeepChem open source library). MoleculeNet benchmarks demonstrate that learnable representations are powerful tools for molecular machine learning and broadly offer the best performance. However, this result comes with caveats. Learnable representations still struggle to deal with complex tasks under data scarcity and highly imbalanced classification. For quantum mechanical and biophysical datasets, the use of physics-aware featurizations can be more important than choice of particular learning algorithm.

Advancements in neural machinery have led to a wide range of algorithmic solutions for molecular property prediction. Two classes of models in particular have yielded promising results: neural networks applied to computed molecular fingerprints or expert-crafted descriptors, and graph convolutional neural networks that construct a learned molecular representation by operating on the graph structure of the molecule. However, recent literature has yet to clearly determine which of these two methods is superior when generalizing to new chemical space. Furthermore, prior research has rarely examined these new models in industry research settings in comparison to existing employed models. In this paper, we benchmark models extensively on 19 public and 16 proprietary industrial datasets spanning a wide variety of chemical endpoints. In addition, we introduce a graph convolutional model that consistently matches or outperforms models using fixed molecular descriptors as well as previous graph neural architectures on both public and proprietary datasets. Our empirical findings indicate that while approaches based on these representations have yet to reach the level of experimental reproducibility, our proposed model nevertheless offers significant improvements over models currently used in industrial workflows.

Self-supervised learning has recently gained growing interest in molecular modeling for scientific tasks such as AI-assisted drug discovery. Current studies consider leveraging both 2D and 3D molecular structures for representation learning. However, relying on straightforward alignment strategies that treat each modality separately, these methods fail to exploit the intrinsic correlation between 2D and 3D representations that reflect the underlying structural characteristics of molecules, and only perform coarse-grained molecule-level alignment. To derive fine-grained alignment and promote structural molecule understanding, we introduce an atomic-relation level "blend-then-predict" self-supervised learning approach, MoleBLEND, which first blends atom relations represented by different modalities into one unified relation matrix for joint encoding, then recovers modality-specific information for 2D and 3D structures individually. By treating atom relationships as anchors, MoleBLEND organically aligns and integrates visually dissimilar 2D and 3D modalities of the same molecule at fine-grained atomic level, painting a more comprehensive depiction of each molecule. Extensive experiments show that MoleBLEND achieves state-of-the-art performance across major 2D/3D molecular benchmarks. We further provide theoretical insights from the perspective of mutual-information maximization, demonstrating that our method unifies contrastive, generative (cross-modality prediction) and mask-then-predict (single-modality prediction) objectives into one single cohesive framework.

Models based on machine learning can enable accurate and fast molecular property predictions, which is of interest in drug discovery and material design. Various supervised machine learning models have demonstrated promising performance, but the vast chemical space and the limited availability of property labels make supervised learning challenging. Recently, unsupervised transformer-based language models pretrained on a large unlabelled corpus have produced state-of-the-art results in many downstream natural language processing tasks. Inspired by this development, we present molecular embeddings obtained by training an efficient transformer encoder model, MoLFormer, which uses rotary positional embeddings. This model employs a linear attention mechanism, coupled with highly distributed training, on SMILES sequences of 1.1 billion unlabelled molecules from the PubChem and ZINC datasets. We show that the learned molecular representation outperforms existing baselines, including supervised and self-supervised graph neural networks and language models, on several downstream tasks from ten benchmark datasets. They perform competitively on two others. Further analyses, specifically through the lens of attention, demonstrate that MoLFormer trained on chemical SMILES indeed learns the spatial relationships between atoms within a molecule. These results provide encouraging evidence that large-scale molecular language models can capture sufficient chemical and structural information to predict various distinct molecular properties, including quantum-chemical properties.

Molecule pretraining has quickly become the go-to schema to boost the performance of AI-based drug discovery. Naturally, molecules can be represented as 2D topological graphs or 3D geometric point clouds. Although most existing pertaining methods focus on merely the single modality, recent research has shown that maximizing the mutual information (MI) between such two modalities enhances the molecule representation ability. Meanwhile, existing molecule multi-modal pretraining approaches approximate MI based on the representation space encoded from the topology and geometry, thus resulting in the loss of critical structural information of molecules. To address this issue, we propose MoleculeSDE. MoleculeSDE leverages group symmetric (e.g., SE(3)-equivariant and reflection-antisymmetric) stochastic differential equation models to generate the 3D geometries from 2D topologies, and vice versa, directly in the input space. It not only obtains tighter MI bound but also enables prosperous downstream tasks than the previous work. By comparing with 17 pretraining baselines, we empirically verify that MoleculeSDE can learn an expressive representation with state-of-the-art performance on 26 out of 32 downstream tasks.

Large-scale pre-training methodologies for chemical language models represent a breakthrough in cheminformatics. These methods excel in tasks such as property prediction and molecule generation by learning contextualized representations of input tokens through self-supervised learning on large unlabeled corpora. Typically, this involves pre-training on unlabeled data followed by fine-tuning on specific tasks, reducing dependence on annotated datasets and broadening chemical language representation understanding. This paper introduces a large encoder-decoder chemical foundation models pre-trained on a curated dataset of 91 million SMILES samples sourced from PubChem, which is equivalent to 4 billion of molecular tokens. The proposed foundation model supports different complex tasks, including quantum property prediction, and offer flexibility with two main variants (289M and 8times289M). Our experiments across multiple benchmark datasets validate the capacity of the proposed model in providing state-of-the-art results for different tasks. We also provide a preliminary assessment of the compositionality of the embedding space as a prerequisite for the reasoning tasks. We demonstrate that the produced latent space is separable compared to the state-of-the-art with few-shot learning capabilities.

Molecules are frequently represented as graphs, but the underlying 3D molecular geometry (the locations of the atoms) ultimately determines most molecular properties. However, most molecules are not static and at room temperature adopt a wide variety of geometries or conformations. The resulting distribution on geometries p(x) is known as the Boltzmann distribution, and many molecular properties are expectations computed under this distribution. Generating accurate samples from the Boltzmann distribution is therefore essential for computing these expectations accurately. Traditional sampling-based methods are computationally expensive, and most recent machine learning-based methods have focused on identifying modes in this distribution rather than generating true samples. Generating such samples requires capturing conformational variability, and it has been widely recognized that the majority of conformational variability in molecules arises from rotatable bonds. In this work, we present VonMisesNet, a new graph neural network that captures conformational variability via a variational approximation of rotatable bond torsion angles as a mixture of von Mises distributions. We demonstrate that VonMisesNet can generate conformations for arbitrary molecules in a way that is both physically accurate with respect to the Boltzmann distribution and orders of magnitude faster than existing sampling methods.

Deep learning in computational biochemistry has traditionally focused on molecular graphs neural representations; however, recent advances in language models highlight how much scientific knowledge is encoded in text. To bridge these two modalities, we investigate how molecular property information can be transferred from natural language to graph representations. We study property prediction performance gains after using contrastive learning to align neural graph representations with representations of textual descriptions of their characteristics. We implement neural relevance scoring strategies to improve text retrieval, introduce a novel chemically-valid molecular graph augmentation strategy inspired by organic reactions, and demonstrate improved performance on downstream MoleculeNet property classification tasks. We achieve a +4.26% AUROC gain versus models pre-trained on the graph modality alone, and a +1.54% gain compared to recently proposed molecular graph/text contrastively trained MoMu model (Su et al. 2022).

Molecular representation is a foundational element in our understanding of the physical world. Its importance ranges from the fundamentals of chemical reactions to the design of new therapies and materials. Previous molecular machine learning models have employed strings, fingerprints, global features, and simple molecular graphs that are inherently information-sparse representations. However, as the complexity of prediction tasks increases, the molecular representation needs to encode higher fidelity information. This work introduces a novel approach to infusing quantum-chemical-rich information into molecular graphs via stereoelectronic effects. We show that the explicit addition of stereoelectronic interactions significantly improves the performance of molecular machine learning models. Furthermore, stereoelectronics-infused representations can be learned and deployed with a tailored double graph neural network workflow, enabling its application to any downstream molecular machine learning task. Finally, we show that the learned representations allow for facile stereoelectronic evaluation of previously intractable systems, such as entire proteins, opening new avenues of molecular design.

Generating molecules with high binding affinities to target proteins (a.k.a. structure-based drug design) is a fundamental and challenging task in drug discovery. Recently, deep generative models have achieved remarkable success in generating 3D molecules conditioned on the protein pocket. However, most existing methods consider molecular generation for protein pockets independently while neglecting the underlying connections such as subpocket-level similarities. Subpockets are the local protein environments of ligand fragments and pockets with similar subpockets may bind the same molecular fragment (motif) even though their overall structures are different. Therefore, the trained models can hardly generalize to unseen protein pockets in real-world applications. In this paper, we propose a novel method DrugGPS for generalizable structure-based drug design. With the biochemical priors, we propose to learn subpocket prototypes and construct a global interaction graph to model the interactions between subpocket prototypes and molecular motifs. Moreover, a hierarchical graph transformer encoder and motif-based 3D molecule generation scheme are used to improve the model's performance. The experimental results show that our model consistently outperforms baselines in generating realistic drug candidates with high affinities in challenging out-of-distribution settings.

Predicting drug efficacy and safety in vivo requires information on biological responses (e.g., cell morphology and gene expression) to small molecule perturbations. However, current molecular representation learning methods do not provide a comprehensive view of cell states under these perturbations and struggle to remove noise, hindering model generalization. We introduce the Information Alignment (InfoAlign) approach to learn molecular representations through the information bottleneck method in cells. We integrate molecules and cellular response data as nodes into a context graph, connecting them with weighted edges based on chemical, biological, and computational criteria. For each molecule in a training batch, InfoAlign optimizes the encoder's latent representation with a minimality objective to discard redundant structural information. A sufficiency objective decodes the representation to align with different feature spaces from the molecule's neighborhood in the context graph. We demonstrate that the proposed sufficiency objective for alignment is tighter than existing encoder-based contrastive methods. Empirically, we validate representations from InfoAlign in two downstream tasks: molecular property prediction against up to 19 baseline methods across four datasets, plus zero-shot molecule-morphology matching.

Graph neural networks are emerging as promising methods for modeling molecular graphs, in which nodes and edges correspond to atoms and chemical bonds, respectively. Recent studies show that when 3D molecular geometries, such as bond lengths and angles, are available, molecular property prediction tasks can be made more accurate. However, computing of 3D molecular geometries requires quantum calculations that are computationally prohibitive. For example, accurate calculation of 3D geometries of a small molecule requires hours of computing time using density functional theory (DFT). Here, we propose to predict the ground-state 3D geometries from molecular graphs using machine learning methods. To make this feasible, we develop a benchmark, known as Molecule3D, that includes a dataset with precise ground-state geometries of approximately 4 million molecules derived from DFT. We also provide a set of software tools for data processing, splitting, training, and evaluation, etc. Specifically, we propose to assess the error and validity of predicted geometries using four metrics. We implement two baseline methods that either predict the pairwise distance between atoms or atom coordinates in 3D space. Experimental results show that, compared with generating 3D geometries with RDKit, our method can achieve comparable prediction accuracy but with much smaller computational costs. Our Molecule3D is available as a module of the MoleculeX software library (https://github.com/divelab/MoleculeX).

While artificial intelligence has made remarkable strides in revealing the relationship between biological macromolecules' primary sequence and tertiary structure, designing RNA sequences based on specified tertiary structures remains challenging. Though existing approaches in protein design have thoroughly explored structure-to-sequence dependencies in proteins, RNA design still confronts difficulties due to structural complexity and data scarcity. Moreover, direct transplantation of protein design methodologies into RNA design fails to achieve satisfactory outcomes although sharing similar structural components. In this study, we aim to systematically construct a data-driven RNA design pipeline. We crafted a large, well-curated benchmark dataset and designed a comprehensive structural modeling approach to represent the complex RNA tertiary structure. More importantly, we proposed a hierarchical data-efficient representation learning framework that learns structural representations through contrastive learning at both cluster-level and sample-level to fully leverage the limited data. By constraining data representations within a limited hyperspherical space, the intrinsic relationships between data points could be explicitly imposed. Moreover, we incorporated extracted secondary structures with base pairs as prior knowledge to facilitate the RNA design process. Extensive experiments demonstrate the effectiveness of our proposed method, providing a reliable baseline for future RNA design tasks. The source code and benchmark dataset are available at https://github.com/A4Bio/RDesign.

Molecular "fingerprints" encoding structural information are the workhorse of cheminformatics and machine learning in drug discovery applications. However, fingerprint representations necessarily emphasize particular aspects of the molecular structure while ignoring others, rather than allowing the model to make data-driven decisions. We describe molecular "graph convolutions", a machine learning architecture for learning from undirected graphs, specifically small molecules. Graph convolutions use a simple encoding of the molecular graph---atoms, bonds, distances, etc.---which allows the model to take greater advantage of information in the graph structure. Although graph convolutions do not outperform all fingerprint-based methods, they (along with other graph-based methods) represent a new paradigm in ligand-based virtual screening with exciting opportunities for future improvement.

We present MolT5 - a self-supervised learning framework for pretraining models on a vast amount of unlabeled natural language text and molecule strings. MolT5 allows for new, useful, and challenging analogs of traditional vision-language tasks, such as molecule captioning and text-based de novo molecule generation (altogether: translation between molecules and language), which we explore for the first time. Since MolT5 pretrains models on single-modal data, it helps overcome the chemistry domain shortcoming of data scarcity. Furthermore, we consider several metrics, including a new cross-modal embedding-based metric, to evaluate the tasks of molecule captioning and text-based molecule generation. Our results show that MolT5-based models are able to generate outputs, both molecules and captions, which in many cases are high quality.

Molecule discovery serves as a cornerstone in numerous scientific domains, fueling the development of new materials and innovative drug designs. Recent developments of in-silico molecule discovery have highlighted the promising results of cross-modal techniques, which bridge molecular structures with their descriptive annotations. However, these cross-modal methods frequently encounter the issue of data scarcity, hampering their performance and application. In this paper, we address the low-resource challenge by utilizing artificially-real data generated by Large Language Models (LLMs). We first introduce a retrieval-based prompting strategy to construct high-quality pseudo data, then explore the optimal method to effectively leverage this pseudo data. Experiments show that using pseudo data for domain adaptation outperforms all existing methods, while also requiring a smaller model scale, reduced data size and lower training cost, highlighting its efficiency. Furthermore, our method shows a sustained improvement as the volume of pseudo data increases, revealing the great potential of pseudo data in advancing low-resource cross-modal molecule discovery.

Machine learning, notably deep learning, has significantly propelled molecular investigations within the biochemical sphere. Traditionally, modeling for such research has centered around a handful of paradigms. For instance, the prediction paradigm is frequently deployed for tasks such as molecular property prediction. To enhance the generation and decipherability of purely data-driven models, scholars have integrated biochemical domain knowledge into these molecular study models. This integration has sparked a surge in paradigm transfer, which is solving one molecular learning task by reformulating it as another one. With the emergence of Large Language Models, these paradigms have demonstrated an escalating trend towards harmonized unification. In this work, we delineate a literature survey focused on knowledge-informed molecular learning from the perspective of paradigm transfer. We classify the paradigms, scrutinize their methodologies, and dissect the contribution of domain knowledge. Moreover, we encapsulate prevailing trends and identify intriguing avenues for future exploration in molecular learning.

Establishing the relationship between 3D structures and the energy states of molecular systems has proven to be a promising approach for learning 3D molecular representations. However, existing methods are limited to modeling the molecular energy states from classical mechanics. This limitation results in a significant oversight of quantum mechanical effects, such as quantized (discrete) energy level structures, which offer a more accurate estimation of molecular energy and can be experimentally measured through energy spectra. In this paper, we propose to utilize the energy spectra to enhance the pre-training of 3D molecular representations (MolSpectra), thereby infusing the knowledge of quantum mechanics into the molecular representations. Specifically, we propose SpecFormer, a multi-spectrum encoder for encoding molecular spectra via masked patch reconstruction. By further aligning outputs from the 3D encoder and spectrum encoder using a contrastive objective, we enhance the 3D encoder's understanding of molecules. Evaluations on public benchmarks reveal that our pre-trained representations surpass existing methods in predicting molecular properties and modeling dynamics.

This paper challenges the recent paradigm in atomic property prediction that links progress to growing dataset sizes and computational resources. We show that pretraining on a carefully selected, task-relevant dataset can match or even surpass large-scale pretraining, while using as little as 1/24th of the computational cost. We introduce the Chemical Similarity Index (CSI), a novel metric inspired by computer vision's Fr\'echet Inception Distance, for molecular graphs which quantifies the alignment between upstream pretraining datasets and downstream tasks. By selecting the most relevant dataset with minimal CSI distance, we show that models pretrained on a smaller, focused dataset consistently outperform those pretrained on massive, mixed datasets such as JMP, even when those larger datasets include the relevant dataset. Counterintuitively, we also find that indiscriminately adding more data can degrade model performance when the additional data poorly aligns with the task at hand. Our findings highlight that quality often outperforms quantity in pretraining for atomic property prediction.

With the surge in available data from various modalities, there is a growing need to bridge the gap between different data types. In this work, we introduce a novel approach to learn cross-modal representations between image data and molecular representations for drug discovery. We propose EMM and IMM, two innovative loss functions built on top of CLIP that leverage weak supervision and cross sites replicates in High-Content Screening. Evaluating our model against known baseline on cross-modal retrieval, we show that our proposed approach allows to learn better representations and mitigate batch effect. In addition, we also present a preprocessing method for the JUMP-CP dataset that effectively reduce the required space from 85Tb to a mere usable 7Tb size, still retaining all perturbations and most of the information content.

Modeling the energy and forces of atomic systems is a fundamental problem in computational chemistry with the potential to help address many of the world's most pressing problems, including those related to energy scarcity and climate change. These calculations are traditionally performed using Density Functional Theory, which is computationally very expensive. Machine learning has the potential to dramatically improve the efficiency of these calculations from days or hours to seconds. We propose the Spherical Channel Network (SCN) to model atomic energies and forces. The SCN is a graph neural network where nodes represent atoms and edges their neighboring atoms. The atom embeddings are a set of spherical functions, called spherical channels, represented using spherical harmonics. We demonstrate, that by rotating the embeddings based on the 3D edge orientation, more information may be utilized while maintaining the rotational equivariance of the messages. While equivariance is a desirable property, we find that by relaxing this constraint in both message passing and aggregation, improved accuracy may be achieved. We demonstrate state-of-the-art results on the large-scale Open Catalyst dataset in both energy and force prediction for numerous tasks and metrics.

This paper introduces M^{3}-20M, a large-scale Multi-Modal Molecular dataset that contains over 20 million molecules. Designed to support AI-driven drug design and discovery, M^{3}-20M is 71 times more in the number of molecules than the largest existing dataset, providing an unprecedented scale that can highly benefit training or fine-tuning large (language) models with superior performance for drug design and discovery. This dataset integrates one-dimensional SMILES, two-dimensional molecular graphs, three-dimensional molecular structures, physicochemical properties, and textual descriptions collected through web crawling and generated by using GPT-3.5, offering a comprehensive view of each molecule. To demonstrate the power of M^{3}-20M in drug design and discovery, we conduct extensive experiments on two key tasks: molecule generation and molecular property prediction, using large language models including GLM4, GPT-3.5, and GPT-4. Our experimental results show that M^{3}-20M can significantly boost model performance in both tasks. Specifically, it enables the models to generate more diverse and valid molecular structures and achieve higher property prediction accuracy than the existing single-modal datasets, which validates the value and potential of M^{3}-20M in supporting AI-driven drug design and discovery. The dataset is available at https://github.com/bz99bz/M-3.

We introduce a new framework for molecular graph generation with 3D molecular generative models. Our Synthetic Coordinate Embedding (SyCo) framework maps molecular graphs to Euclidean point clouds via synthetic conformer coordinates and learns the inverse map using an E(n)-Equivariant Graph Neural Network (EGNN). The induced point cloud-structured latent space is well-suited to apply existing 3D molecular generative models. This approach simplifies the graph generation problem - without relying on molecular fragments nor autoregressive decoding - into a point cloud generation problem followed by node and edge classification tasks. Further, we propose a novel similarity-constrained optimization scheme for 3D diffusion models based on inpainting and guidance. As a concrete implementation of our framework, we develop EDM-SyCo based on the E(3) Equivariant Diffusion Model (EDM). EDM-SyCo achieves state-of-the-art performance in distribution learning of molecular graphs, outperforming the best non-autoregressive methods by more than 30% on ZINC250K and 16% on the large-scale GuacaMol dataset while improving conditional generation by up to 3.9 times.

Generative models are becoming a tool of choice for exploring the molecular space. These models learn on a large training dataset and produce novel molecular structures with similar properties. Generated structures can be utilized for virtual screening or training semi-supervised predictive models in the downstream tasks. While there are plenty of generative models, it is unclear how to compare and rank them. In this work, we introduce a benchmarking platform called Molecular Sets (MOSES) to standardize training and comparison of molecular generative models. MOSES provides a training and testing datasets, and a set of metrics to evaluate the quality and diversity of generated structures. We have implemented and compared several molecular generation models and suggest to use our results as reference points for further advancements in generative chemistry research. The platform and source code are available at https://github.com/molecularsets/moses.

Molecular structure recognition is the task of translating a molecular image into its graph structure. Significant variation in drawing styles and conventions exhibited in chemical literature poses a significant challenge for automating this task. In this paper, we propose MolScribe, a novel image-to-graph generation model that explicitly predicts atoms and bonds, along with their geometric layouts, to construct the molecular structure. Our model flexibly incorporates symbolic chemistry constraints to recognize chirality and expand abbreviated structures. We further develop data augmentation strategies to enhance the model robustness against domain shifts. In experiments on both synthetic and realistic molecular images, MolScribe significantly outperforms previous models, achieving 76-93% accuracy on public benchmarks. Chemists can also easily verify MolScribe's prediction, informed by its confidence estimation and atom-level alignment with the input image. MolScribe is publicly available through Python and web interfaces: https://github.com/thomas0809/MolScribe.

Methods of computational quantum chemistry provide accurate approximations of molecular properties crucial for computer-aided drug discovery and other areas of chemical science. However, high computational complexity limits the scalability of their applications. Neural network potentials (NNPs) are a promising alternative to quantum chemistry methods, but they require large and diverse datasets for training. This work presents a new dataset and benchmark called nabla^2DFT that is based on the nablaDFT. It contains twice as much molecular structures, three times more conformations, new data types and tasks, and state-of-the-art models. The dataset includes energies, forces, 17 molecular properties, Hamiltonian and overlap matrices, and a wavefunction object. All calculations were performed at the DFT level (omegaB97X-D/def2-SVP) for each conformation. Moreover, nabla^2DFT is the first dataset that contains relaxation trajectories for a substantial number of drug-like molecules. We also introduce a novel benchmark for evaluating NNPs in molecular property prediction, Hamiltonian prediction, and conformational optimization tasks. Finally, we propose an extendable framework for training NNPs and implement 10 models within it.

Generative models for molecules have shown considerable promise for use in computational chemistry, but remain difficult to use for non-experts. For this reason, we introduce open-source infrastructure for easily building generative molecular models into the widely used DeepChem [Ramsundar et al., 2019] library with the aim of creating a robust and reusable molecular generation pipeline. In particular, we add high quality PyTorch [Paszke et al., 2019] implementations of the Molecular Generative Adversarial Networks (MolGAN) [Cao and Kipf, 2022] and Normalizing Flows [Papamakarios et al., 2021]. Our implementations show strong performance comparable with past work [Kuznetsov and Polykovskiy, 2021, Cao and Kipf, 2022].

Identifying the chemical structure from a graphical representation, or image, of a molecule is a challenging pattern recognition task that would greatly benefit drug development. Yet, existing methods for chemical structure recognition do not typically generalize well, and show diminished effectiveness when confronted with domains where data is sparse, or costly to generate, such as hand-drawn molecule images. To address this limitation, we propose a new chemical structure recognition tool that delivers state-of-the-art performance and can adapt to new domains with a limited number of data samples and supervision. Unlike previous approaches, our method provides atom-level localization, and can therefore segment the image into the different atoms and bonds. Our model is the first model to perform OCSR with atom-level entity detection with only SMILES supervision. Through rigorous and extensive benchmarking, we demonstrate the preeminence of our chemical structure recognition approach in terms of data efficiency, accuracy, and atom-level entity prediction.

The development of efficient machine learning models for molecular systems representation is becoming crucial in scientific research. We introduce TensorNet, an innovative O(3)-equivariant message-passing neural network architecture that leverages Cartesian tensor representations. By using Cartesian tensor atomic embeddings, feature mixing is simplified through matrix product operations. Furthermore, the cost-effective decomposition of these tensors into rotation group irreducible representations allows for the separate processing of scalars, vectors, and tensors when necessary. Compared to higher-rank spherical tensor models, TensorNet demonstrates state-of-the-art performance with significantly fewer parameters. For small molecule potential energies, this can be achieved even with a single interaction layer. As a result of all these properties, the model's computational cost is substantially decreased. Moreover, the accurate prediction of vector and tensor molecular quantities on top of potential energies and forces is possible. In summary, TensorNet's framework opens up a new space for the design of state-of-the-art equivariant models.

Deep graph generative modeling has proven capable of learning the distribution of complex, multi-scale structures characterizing real-world graphs. However, one of the main limitations of existing methods is their large output space, which limits generation scalability and hinders accurate modeling of the underlying distribution. To overcome these limitations, we propose a novel approach that significantly reduces the output space of existing graph generative models. Specifically, starting from the observation that many real-world graphs have low graph bandwidth, we restrict graph bandwidth during training and generation. Our strategy improves both generation scalability and quality without increasing architectural complexity or reducing expressiveness. Our approach is compatible with existing graph generative methods, and we describe its application to both autoregressive and one-shot models. We extensively validate our strategy on synthetic and real datasets, including molecular graphs. Our experiments show that, in addition to improving generation efficiency, our approach consistently improves generation quality and reconstruction accuracy. The implementation is made available.

Generating novel active molecules for a given protein is an extremely challenging task for generative models that requires an understanding of the complex physical interactions between the molecule and its environment. In this paper, we present a novel generative model, BindGPT which uses a conceptually simple but powerful approach to create 3D molecules within the protein's binding site. Our model produces molecular graphs and conformations jointly, eliminating the need for an extra graph reconstruction step. We pretrain BindGPT on a large-scale dataset and fine-tune it with reinforcement learning using scores from external simulation software. We demonstrate how a single pretrained language model can serve at the same time as a 3D molecular generative model, conformer generator conditioned on the molecular graph, and a pocket-conditioned 3D molecule generator. Notably, the model does not make any representational equivariance assumptions about the domain of generation. We show how such simple conceptual approach combined with pretraining and scaling can perform on par or better than the current best specialized diffusion models, language models, and graph neural networks while being two orders of magnitude cheaper to sample.

Molecular representation learning contributes to multiple downstream tasks such as molecular property prediction and drug design. To properly represent molecules, graph contrastive learning is a promising paradigm as it utilizes self-supervision signals and has no requirements for human annotations. However, prior works fail to incorporate fundamental domain knowledge into graph semantics and thus ignore the correlations between atoms that have common attributes but are not directly connected by bonds. To address these issues, we construct a Chemical Element Knowledge Graph (KG) to summarize microscopic associations between elements and propose a novel Knowledge-enhanced Contrastive Learning (KCL) framework for molecular representation learning. KCL framework consists of three modules. The first module, knowledge-guided graph augmentation, augments the original molecular graph based on the Chemical Element KG. The second module, knowledge-aware graph representation, extracts molecular representations with a common graph encoder for the original molecular graph and a Knowledge-aware Message Passing Neural Network (KMPNN) to encode complex information in the augmented molecular graph. The final module is a contrastive objective, where we maximize agreement between these two views of molecular graphs. Extensive experiments demonstrated that KCL obtained superior performances against state-of-the-art baselines on eight molecular datasets. Visualization experiments properly interpret what KCL has learned from atoms and attributes in the augmented molecular graphs. Our codes and data are available at https://github.com/ZJU-Fangyin/KCL.

Traditional molecular string representations, such as SMILES, often pose challenges for AI-driven molecular design due to their non-sequential depiction of molecular substructures. To address this issue, we introduce Sequential Attachment-based Fragment Embedding (SAFE), a novel line notation for chemical structures. SAFE reimagines SMILES strings as an unordered sequence of interconnected fragment blocks while maintaining full compatibility with existing SMILES parsers. It streamlines complex generative tasks, including scaffold decoration, fragment linking, polymer generation, and scaffold hopping, while facilitating autoregressive generation for fragment-constrained design, thereby eliminating the need for intricate decoding or graph-based models. We demonstrate the effectiveness of SAFE by training an 87-million-parameter GPT2-like model on a dataset containing 1.1 billion SAFE representations. Through extensive experimentation, we show that our SAFE-GPT model exhibits versatile and robust optimization performance. SAFE opens up new avenues for the rapid exploration of chemical space under various constraints, promising breakthroughs in AI-driven molecular design.

Motivation: The development of novel compounds targeting proteins of interest is one of the most important tasks in the pharmaceutical industry. Deep generative models have been applied to targeted molecular design and have shown promising results. Recently, target-specific molecule generation has been viewed as a translation between the protein language and the chemical language. However, such a model is limited by the availability of interacting protein-ligand pairs. On the other hand, large amounts of unlabeled protein sequences and chemical compounds are available and have been used to train language models that learn useful representations. In this study, we propose exploiting pretrained biochemical language models to initialize (i.e. warm start) targeted molecule generation models. We investigate two warm start strategies: (i) a one-stage strategy where the initialized model is trained on targeted molecule generation (ii) a two-stage strategy containing a pre-finetuning on molecular generation followed by target specific training. We also compare two decoding strategies to generate compounds: beam search and sampling. Results: The results show that the warm-started models perform better than a baseline model trained from scratch. The two proposed warm-start strategies achieve similar results to each other with respect to widely used metrics from benchmarks. However, docking evaluation of the generated compounds for a number of novel proteins suggests that the one-stage strategy generalizes better than the two-stage strategy. Additionally, we observe that beam search outperforms sampling in both docking evaluation and benchmark metrics for assessing compound quality. Availability and implementation: The source code is available at https://github.com/boun-tabi/biochemical-lms-for-drug-design and the materials are archived in Zenodo at https://doi.org/10.5281/zenodo.6832145

Generative molecular design has moved from proof-of-concept to real-world applicability, as marked by the surge in very recent papers reporting experimental validation. Key challenges in explainability and sample efficiency present opportunities to enhance generative design to directly optimize expensive high-fidelity oracles and provide actionable insights to domain experts. Here, we propose Beam Enumeration to exhaustively enumerate the most probable sub-sequences from language-based molecular generative models and show that molecular substructures can be extracted. When coupled with reinforcement learning, extracted substructures become meaningful, providing a source of explainability and improving sample efficiency through self-conditioned generation. Beam Enumeration is generally applicable to any language-based molecular generative model and notably further improves the performance of the recently reported Augmented Memory algorithm, which achieved the new state-of-the-art on the Practical Molecular Optimization benchmark for sample efficiency. The combined algorithm generates more high reward molecules and faster, given a fixed oracle budget. Beam Enumeration shows that improvements to explainability and sample efficiency for molecular design can be made synergistic.

Molecular dynamics (MD) is a powerful technique for studying microscopic phenomena, but its computational cost has driven significant interest in the development of deep learning-based surrogate models. We introduce generative modeling of molecular trajectories as a paradigm for learning flexible multi-task surrogate models of MD from data. By conditioning on appropriately chosen frames of the trajectory, we show such generative models can be adapted to diverse tasks such as forward simulation, transition path sampling, and trajectory upsampling. By alternatively conditioning on part of the molecular system and inpainting the rest, we also demonstrate the first steps towards dynamics-conditioned molecular design. We validate the full set of these capabilities on tetrapeptide simulations and show that our model can produce reasonable ensembles of protein monomers. Altogether, our work illustrates how generative modeling can unlock value from MD data towards diverse downstream tasks that are not straightforward to address with existing methods or even MD itself. Code is available at https://github.com/bjing2016/mdgen.

Conventional representation learning algorithms for knowledge graphs (KG) map each entity to a unique embedding vector. Such a shallow lookup results in a linear growth of memory consumption for storing the embedding matrix and incurs high computational costs when working with real-world KGs. Drawing parallels with subword tokenization commonly used in NLP, we explore the landscape of more parameter-efficient node embedding strategies with possibly sublinear memory requirements. To this end, we propose NodePiece, an anchor-based approach to learn a fixed-size entity vocabulary. In NodePiece, a vocabulary of subword/sub-entity units is constructed from anchor nodes in a graph with known relation types. Given such a fixed-size vocabulary, it is possible to bootstrap an encoding and embedding for any entity, including those unseen during training. Experiments show that NodePiece performs competitively in node classification, link prediction, and relation prediction tasks while retaining less than 10% of explicit nodes in a graph as anchors and often having 10x fewer parameters. To this end, we show that a NodePiece-enabled model outperforms existing shallow models on a large OGB WikiKG 2 graph having 70x fewer parameters.

Large pretrained models such as GPT-3 have had tremendous impact on modern natural language processing by leveraging self-supervised learning to learn salient representations that can be used to readily finetune on a wide variety of downstream tasks. We investigate the possibility of transferring such advances to molecular machine learning by building a chemical foundation model, ChemBERTa-2, using the language of SMILES. While labeled data for molecular prediction tasks is typically scarce, libraries of SMILES strings are readily available. In this work, we build upon ChemBERTa by optimizing the pretraining process. We compare multi-task and self-supervised pretraining by varying hyperparameters and pretraining dataset size, up to 77M compounds from PubChem. To our knowledge, the 77M set constitutes one of the largest datasets used for molecular pretraining to date. We find that with these pretraining improvements, we are competitive with existing state-of-the-art architectures on the MoleculeNet benchmark suite. We analyze the degree to which improvements in pretraining translate to improvement on downstream tasks.

In recent decades, chemistry publications and patents have increased rapidly. A significant portion of key information is embedded in molecular structure figures, complicating large-scale literature searches and limiting the application of large language models in fields such as biology, chemistry, and pharmaceuticals. The automatic extraction of precise chemical structures is of critical importance. However, the presence of numerous Markush structures in real-world documents, along with variations in molecular image quality, drawing styles, and noise, significantly limits the performance of existing optical chemical structure recognition (OCSR) methods. We present MolParser, a novel end-to-end OCSR method that efficiently and accurately recognizes chemical structures from real-world documents, including difficult Markush structure. We use a extended SMILES encoding rule to annotate our training dataset. Under this rule, we build MolParser-7M, the largest annotated molecular image dataset to our knowledge. While utilizing a large amount of synthetic data, we employed active learning methods to incorporate substantial in-the-wild data, specifically samples cropped from real patents and scientific literature, into the training process. We trained an end-to-end molecular image captioning model, MolParser, using a curriculum learning approach. MolParser significantly outperforms classical and learning-based methods across most scenarios, with potential for broader downstream applications. The dataset is publicly available.

Recent advancements in biological research leverage the integration of molecules, proteins, and natural language to enhance drug discovery. However, current models exhibit several limitations, such as the generation of invalid molecular SMILES, underutilization of contextual information, and equal treatment of structured and unstructured knowledge. To address these issues, we propose BioT5, a comprehensive pre-training framework that enriches cross-modal integration in biology with chemical knowledge and natural language associations. BioT5 utilizes SELFIES for 100% robust molecular representations and extracts knowledge from the surrounding context of bio-entities in unstructured biological literature. Furthermore, BioT5 distinguishes between structured and unstructured knowledge, leading to more effective utilization of information. After fine-tuning, BioT5 shows superior performance across a wide range of tasks, demonstrating its strong capability of capturing underlying relations and properties of bio-entities. Our code is available at https://github.com/QizhiPei/BioT5{Github}.

The automatic analysis of chemical literature has immense potential to accelerate the discovery of new materials and drugs. Much of the critical information in patent documents and scientific articles is contained in figures, depicting the molecule structures. However, automatically parsing the exact chemical structure is a formidable challenge, due to the amount of detailed information, the diversity of drawing styles, and the need for training data. In this work, we introduce MolGrapher to recognize chemical structures visually. First, a deep keypoint detector detects the atoms. Second, we treat all candidate atoms and bonds as nodes and put them in a graph. This construct allows a natural graph representation of the molecule. Last, we classify atom and bond nodes in the graph with a Graph Neural Network. To address the lack of real training data, we propose a synthetic data generation pipeline producing diverse and realistic results. In addition, we introduce a large-scale benchmark of annotated real molecule images, USPTO-30K, to spur research on this critical topic. Extensive experiments on five datasets show that our approach significantly outperforms classical and learning-based methods in most settings. Code, models, and datasets are available.

Protein modeling is an increasingly popular area of machine learning research. Semi-supervised learning has emerged as an important paradigm in protein modeling due to the high cost of acquiring supervised protein labels, but the current literature is fragmented when it comes to datasets and standardized evaluation techniques. To facilitate progress in this field, we introduce the Tasks Assessing Protein Embeddings (TAPE), a set of five biologically relevant semi-supervised learning tasks spread across different domains of protein biology. We curate tasks into specific training, validation, and test splits to ensure that each task tests biologically relevant generalization that transfers to real-life scenarios. We benchmark a range of approaches to semi-supervised protein representation learning, which span recent work as well as canonical sequence learning techniques. We find that self-supervised pretraining is helpful for almost all models on all tasks, more than doubling performance in some cases. Despite this increase, in several cases features learned by self-supervised pretraining still lag behind features extracted by state-of-the-art non-neural techniques. This gap in performance suggests a huge opportunity for innovative architecture design and improved modeling paradigms that better capture the signal in biological sequences. TAPE will help the machine learning community focus effort on scientifically relevant problems. Toward this end, all data and code used to run these experiments are available at https://github.com/songlab-cal/tape.

We introduce a convolutional neural network that operates directly on graphs. These networks allow end-to-end learning of prediction pipelines whose inputs are graphs of arbitrary size and shape. The architecture we present generalizes standard molecular feature extraction methods based on circular fingerprints. We show that these data-driven features are more interpretable, and have better predictive performance on a variety of tasks.

GNNs and chemical fingerprints are the predominant approaches to representing molecules for property prediction. However, in NLP, transformers have become the de-facto standard for representation learning thanks to their strong downstream task transfer. In parallel, the software ecosystem around transformers is maturing rapidly, with libraries like HuggingFace and BertViz enabling streamlined training and introspection. In this work, we make one of the first attempts to systematically evaluate transformers on molecular property prediction tasks via our ChemBERTa model. ChemBERTa scales well with pretraining dataset size, offering competitive downstream performance on MoleculeNet and useful attention-based visualization modalities. Our results suggest that transformers offer a promising avenue of future work for molecular representation learning and property prediction. To facilitate these efforts, we release a curated dataset of 77M SMILES from PubChem suitable for large-scale self-supervised pretraining.

We propose a new score-based approach to generate 3D molecules represented as atomic densities on regular grids. First, we train a denoising neural network that learns to map from a smooth distribution of noisy molecules to the distribution of real molecules. Then, we follow the neural empirical Bayes framework [Saremi and Hyvarinen, 2019] and generate molecules in two steps: (i) sample noisy density grids from a smooth distribution via underdamped Langevin Markov chain Monte Carlo, and (ii) recover the ``clean'' molecule by denoising the noisy grid with a single step. Our method, VoxMol, generates molecules in a fundamentally different way than the current state of the art (i.e., diffusion models applied to atom point clouds). It differs in terms of the data representation, the noise model, the network architecture and the generative modeling algorithm. VoxMol achieves comparable results to state of the art on unconditional 3D molecule generation while being simpler to train and faster to generate molecules.

Ligand molecule conformation generation is a critical challenge in drug discovery. Deep learning models have been developed to tackle this problem, particularly through the use of generative models in recent years. However, these models often generate conformations that lack meaningful structure and randomness due to the absence of essential side information. Examples of such side information include the chemical and geometric features of the target protein, ligand-target compound interactions, and ligand chemical properties. Without these constraints, the generated conformations may not be suitable for further selection and design of new drugs. To address this limitation, we propose a novel method for generating ligand conformations that leverage side information and incorporate flexible constraints into standard diffusion models. Drawing inspiration from the concept of message passing, we introduce ligand-target massage passing block, a mechanism that facilitates the exchange of information between target nodes and ligand nodes, thereby incorporating target node features. To capture non-covalent interactions, we introduce ligand-target compound inter and intra edges. To further improve the biological relevance of the generated conformations, we train energy models using scalar chemical features. These models guide the progress of the standard Denoising Diffusion Probabilistic Models, resulting in more biologically meaningful conformations. We evaluate the performance of SIDEGEN using the PDBBind-2020 dataset, comparing it against other methods. The results demonstrate improvements in both Aligned RMSD and Ligand RMSD evaluations. Specifically, our model outperforms GeoDiff (trained on PDBBind-2020) by 20% in terms of the median aligned RMSD metric.

The field of bioinformatics has seen significant progress, making the cross-modal text-molecule retrieval task increasingly vital. This task focuses on accurately retrieving molecule structures based on textual descriptions, by effectively aligning textual descriptions and molecules to assist researchers in identifying suitable molecular candidates. However, many existing approaches overlook the details inherent in molecule sub-structures. In this work, we introduce the Optimal TRansport-based Multi-grained Alignments model (ORMA), a novel approach that facilitates multi-grained alignments between textual descriptions and molecules. Our model features a text encoder and a molecule encoder. The text encoder processes textual descriptions to generate both token-level and sentence-level representations, while molecules are modeled as hierarchical heterogeneous graphs, encompassing atom, motif, and molecule nodes to extract representations at these three levels. A key innovation in ORMA is the application of Optimal Transport (OT) to align tokens with motifs, creating multi-token representations that integrate multiple token alignments with their corresponding motifs. Additionally, we employ contrastive learning to refine cross-modal alignments at three distinct scales: token-atom, multitoken-motif, and sentence-molecule, ensuring that the similarities between correctly matched text-molecule pairs are maximized while those of unmatched pairs are minimized. To our knowledge, this is the first attempt to explore alignments at both the motif and multi-token levels. Experimental results on the ChEBI-20 and PCdes datasets demonstrate that ORMA significantly outperforms existing state-of-the-art (SOTA) models.

A plethora of sentence embedding models makes it challenging to choose one, especially for domains such as telecom, rich with specialized vocabulary. We evaluate multiple embeddings obtained from publicly available models and their domain-adapted variants, on both point retrieval accuracies as well as their (95\%) confidence intervals. We establish a systematic method to obtain thresholds for similarity scores for different embeddings. We observe that fine-tuning improves mean bootstrapped accuracies as well as tightens confidence intervals. The pre-training combined with fine-tuning makes confidence intervals even tighter. To understand these variations, we analyse and report significant correlations between the distributional overlap between top-K, correct and random sentence similarities with retrieval accuracies and similarity thresholds. Following current literature, we analyze if retrieval accuracy variations can be attributed to isotropy of embeddings. Our conclusions are that isotropy of embeddings (as measured by two independent state-of-the-art isotropy metric definitions) cannot be attributed to better retrieval performance. However, domain adaptation which improves retrieval accuracies also improves isotropy. We establish that domain adaptation moves domain specific embeddings further away from general domain embeddings.

Recent neural network-based wave functions have achieved state-of-the-art accuracies in modeling ab-initio ground-state potential energy surface. However, these networks can only solve different spatial arrangements of the same set of atoms. To overcome this limitation, we present Graph-learned orbital embeddings (Globe), a neural network-based reparametrization method that can adapt neural wave functions to different molecules. Globe learns representations of local electronic structures that generalize across molecules via spatial message passing by connecting molecular orbitals to covalent bonds. Further, we propose a size-consistent wave function Ansatz, the Molecular orbital network (Moon), tailored to jointly solve Schr\"odinger equations of different molecules. In our experiments, we find Moon converging in 4.5 times fewer steps to similar accuracy as previous methods or to lower energies given the same time. Further, our analysis shows that Moon's energy estimate scales additively with increased system sizes, unlike previous work where we observe divergence. In both computational chemistry and machine learning, we are the first to demonstrate that a single wave function can solve the Schr\"odinger equation of molecules with different atoms jointly.

The integration of molecule and language has garnered increasing attention in molecular science. Recent advancements in Language Models (LMs) have demonstrated potential for the comprehensive modeling of molecule and language. However, existing works exhibit notable limitations. Most existing works overlook the modeling of 3D information, which is crucial for understanding molecular structures and also functions. While some attempts have been made to leverage external structure encoding modules to inject the 3D molecular information into LMs, there exist obvious difficulties that hinder the integration of molecular structure and language text, such as modality alignment and separate tuning. To bridge this gap, we propose 3D-MolT5, a unified framework designed to model both 1D molecular sequence and 3D molecular structure. The key innovation lies in our methodology for mapping fine-grained 3D substructure representations (based on 3D molecular fingerprints) to a specialized 3D token vocabulary for 3D-MolT5. This 3D structure token vocabulary enables the seamless combination of 1D sequence and 3D structure representations in a tokenized format, allowing 3D-MolT5 to encode molecular sequence (SELFIES), molecular structure, and text sequences within a unified architecture. Alongside, we further introduce 1D and 3D joint pre-training to enhance the model's comprehension of these diverse modalities in a joint representation space and better generalize to various tasks for our foundation model. Through instruction tuning on multiple downstream datasets, our proposed 3D-MolT5 shows superior performance than existing methods in molecular property prediction, molecule captioning, and text-based molecule generation tasks. Our code will be available on GitHub soon.

In this work, we introduce ChemBFN, a language model that handles chemistry tasks based on Bayesian flow networks working on discrete data. A new accuracy schedule is proposed to improve the sampling quality by significantly reducing the reconstruction loss. We show evidence that our method is appropriate for generating molecules with satisfied diversity even when a smaller number of sampling steps is used. A classifier-free guidance method is adapted for conditional generation. It is also worthwhile to point out that after generative training, our model can be fine-tuned on regression and classification tasks with the state-of-the-art performance, which opens the gate of building all-in-one models in a single module style. Our model has been open sourced at https://github.com/Augus1999/bayesian-flow-network-for-chemistry.

Massive molecular simulations of drug-target proteins have been used as a tool to understand disease mechanism and develop therapeutics. This work focuses on learning a generative neural network on a structural ensemble of a drug-target protein, e.g. SARS-CoV-2 Spike protein, obtained from computationally expensive molecular simulations. Model tasks involve characterizing the distinct structural fluctuations of the protein bound to various drug molecules, as well as efficient generation of protein conformations that can serve as an complement of a molecular simulation engine. Specifically, we present a geometric autoencoder framework to learn separate latent space encodings of the intrinsic and extrinsic geometries of the protein structure. For this purpose, the proposed Protein Geometric AutoEncoder (ProGAE) model is trained on the protein contact map and the orientation of the backbone bonds of the protein. Using ProGAE latent embeddings, we reconstruct and generate the conformational ensemble of a protein at or near the experimental resolution, while gaining better interpretability and controllability in term of protein structure generation from the learned latent space. Additionally, ProGAE models are transferable to a different state of the same protein or to a new protein of different size, where only the dense layer decoding from the latent representation needs to be retrained. Results show that our geometric learning-based method enjoys both accuracy and efficiency for generating complex structural variations, charting the path toward scalable and improved approaches for analyzing and enhancing high-cost simulations of drug-target proteins.

In the last few years, graph neural networks (GNNs) have become the standard toolkit for analyzing and learning from data on graphs. This emerging field has witnessed an extensive growth of promising techniques that have been applied with success to computer science, mathematics, biology, physics and chemistry. But for any successful field to become mainstream and reliable, benchmarks must be developed to quantify progress. This led us in March 2020 to release a benchmark framework that i) comprises of a diverse collection of mathematical and real-world graphs, ii) enables fair model comparison with the same parameter budget to identify key architectures, iii) has an open-source, easy-to-use and reproducible code infrastructure, and iv) is flexible for researchers to experiment with new theoretical ideas. As of December 2022, the GitHub repository has reached 2,000 stars and 380 forks, which demonstrates the utility of the proposed open-source framework through the wide usage by the GNN community. In this paper, we present an updated version of our benchmark with a concise presentation of the aforementioned framework characteristics, an additional medium-sized molecular dataset AQSOL, similar to the popular ZINC, but with a real-world measured chemical target, and discuss how this framework can be leveraged to explore new GNN designs and insights. As a proof of value of our benchmark, we study the case of graph positional encoding (PE) in GNNs, which was introduced with this benchmark and has since spurred interest of exploring more powerful PE for Transformers and GNNs in a robust experimental setting.

Transfer learning is a crucial technique for handling a small amount of data that is potentially related to other abundant data. However, most of the existing methods are focused on classification tasks using images and language datasets. Therefore, in order to expand the transfer learning scheme to regression tasks, we propose a novel transfer technique based on differential geometry, namely the Geometrically Aligned Transfer Encoder (GATE). In this method, we interpret the latent vectors from the model to exist on a Riemannian curved manifold. We find a proper diffeomorphism between pairs of tasks to ensure that every arbitrary point maps to a locally flat coordinate in the overlapping region, allowing the transfer of knowledge from the source to the target data. This also serves as an effective regularizer for the model to behave in extrapolation regions. In this article, we demonstrate that GATE outperforms conventional methods and exhibits stable behavior in both the latent space and extrapolation regions for various molecular graph datasets.

Supervised learning on molecules has incredible potential to be useful in chemistry, drug discovery, and materials science. Luckily, several promising and closely related neural network models invariant to molecular symmetries have already been described in the literature. These models learn a message passing algorithm and aggregation procedure to compute a function of their entire input graph. At this point, the next step is to find a particularly effective variant of this general approach and apply it to chemical prediction benchmarks until we either solve them or reach the limits of the approach. In this paper, we reformulate existing models into a single common framework we call Message Passing Neural Networks (MPNNs) and explore additional novel variations within this framework. Using MPNNs we demonstrate state of the art results on an important molecular property prediction benchmark; these results are strong enough that we believe future work should focus on datasets with larger molecules or more accurate ground truth labels.

With the development of computer-assisted techniques, research communities including biochemistry and deep learning have been devoted into the drug discovery field for over a decade. Various applications of deep learning have drawn great attention in drug discovery, such as molecule generation, molecular property prediction, retrosynthesis prediction, and reaction prediction. While most existing surveys only focus on one of the applications, limiting the view of researchers in the community. In this paper, we present a comprehensive review on the aforementioned four aspects, and discuss the relationships among different applications. The latest literature and classical benchmarks are presented for better understanding the development of variety of approaches. We commence by summarizing the molecule representation format in these works, followed by an introduction of recent proposed approaches for each of the four tasks. Furthermore, we review a variety of commonly used datasets and evaluation metrics and compare the performance of deep learning-based models. Finally, we conclude by identifying remaining challenges and discussing the future trend for deep learning methods in drug discovery.

Recently, there has been a surge of interest in employing neural networks for graph generation, a fundamental statistical learning problem with critical applications like molecule design and community analysis. However, most approaches encounter significant limitations when generating large-scale graphs. This is due to their requirement to output the full adjacency matrices whose size grows quadratically with the number of nodes. In response to this challenge, we introduce a new, simple, and scalable graph representation named gap encoded edge list (GEEL) that has a small representation size that aligns with the number of edges. In addition, GEEL significantly reduces the vocabulary size by incorporating the gap encoding and bandwidth restriction schemes. GEEL can be autoregressively generated with the incorporation of node positional encoding, and we further extend GEEL to deal with attributed graphs by designing a new grammar. Our findings reveal that the adoption of this compact representation not only enhances scalability but also bolsters performance by simplifying the graph generation process. We conduct a comprehensive evaluation across ten non-attributed and two molecular graph generation tasks, demonstrating the effectiveness of GEEL.

Recent research trends in computational biology have increasingly focused on integrating text and bio-entity modeling, especially in the context of molecules and proteins. However, previous efforts like BioT5 faced challenges in generalizing across diverse tasks and lacked a nuanced understanding of molecular structures, particularly in their textual representations (e.g., IUPAC). This paper introduces BioT5+, an extension of the BioT5 framework, tailored to enhance biological research and drug discovery. BioT5+ incorporates several novel features: integration of IUPAC names for molecular understanding, inclusion of extensive bio-text and molecule data from sources like bioRxiv and PubChem, the multi-task instruction tuning for generality across tasks, and a novel numerical tokenization technique for improved processing of numerical data. These enhancements allow BioT5+ to bridge the gap between molecular representations and their textual descriptions, providing a more holistic understanding of biological entities, and largely improving the grounded reasoning of bio-text and bio-sequences. The model is pre-trained and fine-tuned with a large number of experiments, including 3 types of problems (classification, regression, generation), 15 kinds of tasks, and 21 total benchmark datasets, demonstrating the remarkable performance and state-of-the-art results in most cases. BioT5+ stands out for its ability to capture intricate relationships in biological data, thereby contributing significantly to bioinformatics and computational biology. Our code is available at https://github.com/QizhiPei/BioT5.

We discover a robust self-supervised strategy tailored towards molecular representations for generative masked language models through a series of tailored, in-depth ablations. Using this pre-training strategy, we train BARTSmiles, a BART-like model with an order of magnitude more compute than previous self-supervised molecular representations. In-depth evaluations show that BARTSmiles consistently outperforms other self-supervised representations across classification, regression, and generation tasks setting a new state-of-the-art on 11 tasks. We then quantitatively show that when applied to the molecular domain, the BART objective learns representations that implicitly encode our downstream tasks of interest. For example, by selecting seven neurons from a frozen BARTSmiles, we can obtain a model having performance within two percentage points of the full fine-tuned model on task Clintox. Lastly, we show that standard attribution interpretability methods, when applied to BARTSmiles, highlight certain substructures that chemists use to explain specific properties of molecules. The code and the pretrained model are publicly available.

We introduce Functional Group-Aware Representations for Small Molecules (FARM), a novel foundation model designed to bridge the gap between SMILES, natural language, and molecular graphs. The key innovation of FARM lies in its functional group-aware tokenization, which incorporates functional group information directly into the representations. This strategic reduction in tokenization granularity in a way that is intentionally interfaced with key drivers of functional properties (i.e., functional groups) enhances the model's understanding of chemical language, expands the chemical lexicon, more effectively bridging SMILES and natural language, and ultimately advances the model's capacity to predict molecular properties. FARM also represents molecules from two perspectives: by using masked language modeling to capture atom-level features and by employing graph neural networks to encode the whole molecule topology. By leveraging contrastive learning, FARM aligns these two views of representations into a unified molecular embedding. We rigorously evaluate FARM on the MoleculeNet dataset, where it achieves state-of-the-art performance on 10 out of 12 tasks. These results highlight FARM's potential to improve molecular representation learning, with promising applications in drug discovery and pharmaceutical research.

Language-molecule models have emerged as an exciting direction for molecular discovery and understanding. However, training these models is challenging due to the scarcity of molecule-language pair datasets. At this point, datasets have been released which are 1) small and scraped from existing databases, 2) large but noisy and constructed by performing entity linking on the scientific literature, and 3) built by converting property prediction datasets to natural language using templates. In this document, we detail the L+M-24 dataset, which has been created for the Language + Molecules Workshop shared task at ACL 2024. In particular, L+M-24 is designed to focus on three key benefits of natural language in molecule design: compositionality, functionality, and abstraction.

Retrosynthesis planning poses a formidable challenge in the organic chemical industry, particularly in pharmaceuticals. Single-step retrosynthesis prediction, a crucial step in the planning process, has witnessed a surge in interest in recent years due to advancements in AI for science. Various deep learning-based methods have been proposed for this task in recent years, incorporating diverse levels of additional chemical knowledge dependency. This paper introduces UAlign, a template-free graph-to-sequence pipeline for retrosynthesis prediction. By combining graph neural networks and Transformers, our method can more effectively leverage the inherent graph structure of molecules. Based on the fact that the majority of molecule structures remain unchanged during a chemical reaction, we propose a simple yet effective SMILES alignment technique to facilitate the reuse of unchanged structures for reactant generation. Extensive experiments show that our method substantially outperforms state-of-the-art template-free and semi-template-based approaches. Importantly, Our template-free method achieves effectiveness comparable to, or even surpasses, established powerful template-based methods. Scientific contribution: We present a novel graph-to-sequence template-free retrosynthesis prediction pipeline that overcomes the limitations of Transformer-based methods in molecular representation learning and insufficient utilization of chemical information. We propose an unsupervised learning mechanism for establishing product-atom correspondence with reactant SMILES tokens, achieving even better results than supervised SMILES alignment methods. Extensive experiments demonstrate that UAlign significantly outperforms state-of-the-art template-free methods and rivals or surpasses template-based approaches, with up to 5\% (top-5) and 5.4\% (top-10) increased accuracy over the strongest baseline.

Generative pre-trained Transformer (GPT) has demonstrates its great success in natural language processing and related techniques have been adapted into molecular modeling. Considering that text is the most important record for scientific discovery, in this paper, we propose MolXPT, a unified language model of text and molecules pre-trained on SMILES (a sequence representation of molecules) wrapped by text. Briefly, we detect the molecule names in each sequence and replace them to the corresponding SMILES. In this way, the SMILES could leverage the information from surrounding text, and vice versa. The above wrapped sequences, text sequences from PubMed and SMILES sequences from PubChem are all fed into a language model for pre-training. Experimental results demonstrate that MolXPT outperforms strong baselines of molecular property prediction on MoleculeNet, performs comparably to the best model in text-molecule translation while using less than half of its parameters, and enables zero-shot molecular generation without finetuning.

Molecular property prediction has gained significant attention due to its transformative potential in multiple scientific disciplines. Conventionally, a molecule graph can be represented either as a graph-structured data or a SMILES text. Recently, the rapid development of Large Language Models (LLMs) has revolutionized the field of NLP. Although it is natural to utilize LLMs to assist in understanding molecules represented by SMILES, the exploration of how LLMs will impact molecular property prediction is still in its early stage. In this work, we advance towards this objective through two perspectives: zero/few-shot molecular classification, and using the new explanations generated by LLMs as representations of molecules. To be specific, we first prompt LLMs to do in-context molecular classification and evaluate their performance. After that, we employ LLMs to generate semantically enriched explanations for the original SMILES and then leverage that to fine-tune a small-scale LM model for multiple downstream tasks. The experimental results highlight the superiority of text explanations as molecular representations across multiple benchmark datasets, and confirm the immense potential of LLMs in molecular property prediction tasks. Codes are available at https://github.com/ChnQ/LLM4Mol.

Identifying a small molecule from its mass spectrum is the primary open problem in computational metabolomics. This is typically cast as information retrieval: an unknown spectrum is matched against spectra predicted computationally from a large database of chemical structures. However, current approaches to spectrum prediction model the output space in ways that force a tradeoff between capturing high resolution mass information and tractable learning. We resolve this tradeoff by casting spectrum prediction as a mapping from an input molecular graph to a probability distribution over molecular formulas. We discover that a large corpus of mass spectra can be closely approximated using a fixed vocabulary constituting only 2% of all observed formulas. This enables efficient spectrum prediction using an architecture similar to graph classification - GrAFF-MS - achieving significantly lower prediction error and orders-of-magnitude faster runtime than state-of-the-art methods.

We resolve difficulties in training and sampling from a discrete generative model by learning a smoothed energy function, sampling from the smoothed data manifold with Langevin Markov chain Monte Carlo (MCMC), and projecting back to the true data manifold with one-step denoising. Our Discrete Walk-Jump Sampling formalism combines the contrastive divergence training of an energy-based model and improved sample quality of a score-based model, while simplifying training and sampling by requiring only a single noise level. We evaluate the robustness of our approach on generative modeling of antibody proteins and introduce the distributional conformity score to benchmark protein generative models. By optimizing and sampling from our models for the proposed distributional conformity score, 97-100% of generated samples are successfully expressed and purified and 70% of functional designs show equal or improved binding affinity compared to known functional antibodies on the first attempt in a single round of laboratory experiments. We also report the first demonstration of long-run fast-mixing MCMC chains where diverse antibody protein classes are visited in a single MCMC chain.

Chemical language models (CLMs) are prominent for their effectiveness in exploring chemical space and enabling molecular engineering. However, while exploring chemical-linguistic space, CLMs suffer from the gap between natural language and molecular representations. This challenge is primarily due to the inherent modeling differences between molecules and texts: molecules operate unified modeling to learn chemical space, while natural language sequentially models the semantic space. Additionally, the limited availability of high-quality text-to-molecule datasets further exacerbates this challenge. To address the problem, we first verified the information bias in molecular representations from different perspectives. We then developed the Heterogeneous Molecular Encoding (HME) framework, a unified molecular encoder compressing the molecular features from fragment sequence, topology, and conformation with Q-learning. To better model chemical-linguistic space, we further constructed the MCMoD dataset, which contains over one million molecules with various conditions, including properties, fragments, and descriptions. Experimentally, HME promotes CLMs to achieve chemical-linguistic sharing space exploration: (1) chemical space exploration with linguistic guidance, where HME achieves significant improvements (+37.8\% FCD) for molecular design in multiple constraints, even in zero-shot scenarios; (2) linguistic space exploration with molecular guidance, where HME generates textual descriptions with high qualities (+11.6\% BLEU) for molecules. These results highlight the precision of HME in handling multi-objective and cross-domain tasks, as well as its remarkable generalization capability on unseen task combinations. HME offers a new perspective on navigating chemical-linguistic sharing space, advancing the potential of CLMs in both fundamental research and practical applications in chemistry.

Molecular conformation optimization is crucial to computer-aided drug discovery and materials design. Traditional energy minimization techniques rely on iterative optimization methods that use molecular forces calculated by a physical simulator (oracle) as anti-gradients. However, this is a computationally expensive approach that requires many interactions with a physical simulator. One way to accelerate this procedure is to replace the physical simulator with a neural network. Despite recent progress in neural networks for molecular conformation energy prediction, such models are prone to distribution shift, leading to inaccurate energy minimization. We find that the quality of energy minimization with neural networks can be improved by providing optimization trajectories as additional training data. Still, it takes around 5 times 10^5 additional conformations to match the physical simulator's optimization quality. In this work, we present the Gradual Optimization Learning Framework (GOLF) for energy minimization with neural networks that significantly reduces the required additional data. The framework consists of an efficient data-collecting scheme and an external optimizer. The external optimizer utilizes gradients from the energy prediction model to generate optimization trajectories, and the data-collecting scheme selects additional training data to be processed by the physical simulator. Our results demonstrate that the neural network trained with GOLF performs on par with the oracle on a benchmark of diverse drug-like molecules using 50x less additional data.

In this paper we tackle the problem of generating conformers of a molecule in 3D space given its molecular graph. We parameterize these conformers as continuous functions that map elements from the molecular graph to points in 3D space. We then formulate the problem of learning to generate conformers as learning a distribution over these functions using a diffusion generative model, called Molecular Conformer Fields (MCF). Our approach is simple and scalable, and achieves state-of-the-art performance on challenging molecular conformer generation benchmarks while making no assumptions about the explicit structure of molecules (e.g. modeling torsional angles). MCF represents an advance in extending diffusion models to handle complex scientific problems in a conceptually simple, scalable and effective manner.

A suitable feature representation that can both preserve the data intrinsic information and reduce data complexity and dimensionality is key to the performance of machine learning models. Deeply rooted in algebraic topology, persistent homology (PH) provides a delicate balance between data simplification and intrinsic structure characterization, and has been applied to various areas successfully. However, the combination of PH and machine learning has been hindered greatly by three challenges, namely topological representation of data, PH-based distance measurements or metrics, and PH-based feature representation. With the development of topological data analysis, progresses have been made on all these three problems, but widely scattered in different literatures. In this paper, we provide a systematical review of PH and PH-based supervised and unsupervised models from a computational perspective. Our emphasizes are the recent development of mathematical models and tools, including PH softwares and PH-based functions, feature representations, kernels, and similarity models. Essentially, this paper can work as a roadmap for the practical application of PH-based machine learning tools. Further, we consider different topological feature representations in different machine learning models, and investigate their impacts on the protein secondary structure classification.

Automated computational analysis of the vast chemical space is critical for numerous fields of research such as drug discovery and material science. Representation learning techniques have recently been employed with the primary objective of generating compact and informative numerical expressions of complex data. One approach to efficiently learn molecular representations is processing string-based notations of chemicals via natural language processing (NLP) algorithms. Majority of the methods proposed so far utilize SMILES notations for this purpose; however, SMILES is associated with numerous problems related to validity and robustness, which may prevent the model from effectively uncovering the knowledge hidden in the data. In this study, we propose SELFormer, a transformer architecture-based chemical language model that utilizes a 100% valid, compact and expressive notation, SELFIES, as input, in order to learn flexible and high-quality molecular representations. SELFormer is pre-trained on two million drug-like compounds and fine-tuned for diverse molecular property prediction tasks. Our performance evaluation has revealed that, SELFormer outperforms all competing methods, including graph learning-based approaches and SMILES-based chemical language models, on predicting aqueous solubility of molecules and adverse drug reactions. We also visualized molecular representations learned by SELFormer via dimensionality reduction, which indicated that even the pre-trained model can discriminate molecules with differing structural properties. We shared SELFormer as a programmatic tool, together with its datasets and pre-trained models. Overall, our research demonstrates the benefit of using the SELFIES notations in the context of chemical language modeling and opens up new possibilities for the design and discovery of novel drug candidates with desired features.

This paper introduces a new model to learn graph neural networks equivariant to rotations, translations, reflections and permutations called E(n)-Equivariant Graph Neural Networks (EGNNs). In contrast with existing methods, our work does not require computationally expensive higher-order representations in intermediate layers while it still achieves competitive or better performance. In addition, whereas existing methods are limited to equivariance on 3 dimensional spaces, our model is easily scaled to higher-dimensional spaces. We demonstrate the effectiveness of our method on dynamical systems modelling, representation learning in graph autoencoders and predicting molecular properties.

Recent advancements in large language models have opened new possibilities for generative molecular drug design. We present Chemlactica and Chemma, two language models fine-tuned on a novel corpus of 110M molecules with computed properties, totaling 40B tokens. These models demonstrate strong performance in generating molecules with specified properties and predicting new molecular characteristics from limited samples. We introduce a novel optimization algorithm that leverages our language models to optimize molecules for arbitrary properties given limited access to a black box oracle. Our approach combines ideas from genetic algorithms, rejection sampling, and prompt optimization. It achieves state-of-the-art performance on multiple molecular optimization benchmarks, including an 8% improvement on Practical Molecular Optimization compared to previous methods. We publicly release the training corpus, the language models and the optimization algorithm.

Molecular relational learning, whose goal is to learn the interaction behavior between molecular pairs, got a surge of interest in molecular sciences due to its wide range of applications. Recently, graph neural networks have recently shown great success in molecular relational learning by modeling a molecule as a graph structure, and considering atom-level interactions between two molecules. Despite their success, existing molecular relational learning methods tend to overlook the nature of chemistry, i.e., a chemical compound is composed of multiple substructures such as functional groups that cause distinctive chemical reactions. In this work, we propose a novel relational learning framework, called CGIB, that predicts the interaction behavior between a pair of graphs by detecting core subgraphs therein. The main idea is, given a pair of graphs, to find a subgraph from a graph that contains the minimal sufficient information regarding the task at hand conditioned on the paired graph based on the principle of conditional graph information bottleneck. We argue that our proposed method mimics the nature of chemical reactions, i.e., the core substructure of a molecule varies depending on which other molecule it interacts with. Extensive experiments on various tasks with real-world datasets demonstrate the superiority of CGIB over state-of-the-art baselines. Our code is available at https://github.com/Namkyeong/CGIB.

Supervised machine learning approaches have been increasingly used in accelerating electronic structure prediction as surrogates of first-principle computational methods, such as density functional theory (DFT). While numerous quantum chemistry datasets focus on chemical properties and atomic forces, the ability to achieve accurate and efficient prediction of the Hamiltonian matrix is highly desired, as it is the most important and fundamental physical quantity that determines the quantum states of physical systems and chemical properties. In this work, we generate a new Quantum Hamiltonian dataset, named as QH9, to provide precise Hamiltonian matrices for 999 or 2998 molecular dynamics trajectories and 130,831 stable molecular geometries, based on the QM9 dataset. By designing benchmark tasks with various molecules, we show that current machine learning models have the capacity to predict Hamiltonian matrices for arbitrary molecules. Both the QH9 dataset and the baseline models are provided to the community through an open-source benchmark, which can be highly valuable for developing machine learning methods and accelerating molecular and materials design for scientific and technological applications. Our benchmark is publicly available at https://github.com/divelab/AIRS/tree/main/OpenDFT/QHBench.

De novo design seeks to generate molecules with required property profiles by virtual design-make-test cycles. With the emergence of deep learning and neural generative models in many application areas, models for molecular design based on neural networks appeared recently and show promising results. However, the new models have not been profiled on consistent tasks, and comparative studies to well-established algorithms have only seldom been performed. To standardize the assessment of both classical and neural models for de novo molecular design, we propose an evaluation framework, GuacaMol, based on a suite of standardized benchmarks. The benchmark tasks encompass measuring the fidelity of the models to reproduce the property distribution of the training sets, the ability to generate novel molecules, the exploration and exploitation of chemical space, and a variety of single and multi-objective optimization tasks. The benchmarking open-source Python code, and a leaderboard can be found on https://benevolent.ai/guacamol

The drug development pipeline for a new compound can last 10-20 years and cost over 10 billion. Drug repurposing offers a more time- and cost-effective alternative. Computational approaches based on biomedical knowledge graph representations have recently yielded new drug repurposing hypotheses. In this study, we present a novel, disease-specific hypergraph representation learning technique to derive contextual embeddings of biological pathways of various lengths but that all start at any given drug and all end at the disease of interest. Further, we extend this method to multi-disease hypergraphs. To determine the repurposing potential of each of the 1,522 drugs, we derive drug-specific distributions of cosine similarity values and ultimately consider the median for ranking. Cosine similarity values are computed between (1) all biological pathways starting at the considered drug and ending at the disease of interest and (2) all biological pathways starting at drugs currently prescribed against that disease and ending at the disease of interest. We illustrate our approach with Alzheimer's disease (AD) and two of its risk factors: hypertension (HTN) and type 2 diabetes (T2D). We compare each drug's rank across four hypergraph settings (single- or multi-disease): AD only, AD + HTN, AD + T2D, and AD + HTN + T2D. Notably, our framework led to the identification of two promising drugs whose repurposing potential was significantly higher in hypergraphs combining two diseases: dapagliflozin (antidiabetic; moved up, from top 32% to top 7%, across all considered drugs) and debrisoquine (antihypertensive; moved up, from top 76% to top 23%). Our approach serves as a hypothesis generation tool, to be paired with a validation pipeline relying on laboratory experiments and semi-automated parsing of the biomedical literature.

Advanced generative model (e.g., diffusion model) derived from simplified continuity assumptions of data distribution, though showing promising progress, has been difficult to apply directly to geometry generation applications due to the multi-modality and noise-sensitive nature of molecule geometry. This work introduces Geometric Bayesian Flow Networks (GeoBFN), which naturally fits molecule geometry by modeling diverse modalities in the differentiable parameter space of distributions. GeoBFN maintains the SE-(3) invariant density modeling property by incorporating equivariant inter-dependency modeling on parameters of distributions and unifying the probabilistic modeling of different modalities. Through optimized training and sampling techniques, we demonstrate that GeoBFN achieves state-of-the-art performance on multiple 3D molecule generation benchmarks in terms of generation quality (90.87% molecule stability in QM9 and 85.6% atom stability in GEOM-DRUG. GeoBFN can also conduct sampling with any number of steps to reach an optimal trade-off between efficiency and quality (e.g., 20-times speedup without sacrificing performance).

Low-dimensional embeddings of nodes in large graphs have proved extremely useful in a variety of prediction tasks, from content recommendation to identifying protein functions. However, most existing approaches require that all nodes in the graph are present during training of the embeddings; these previous approaches are inherently transductive and do not naturally generalize to unseen nodes. Here we present GraphSAGE, a general, inductive framework that leverages node feature information (e.g., text attributes) to efficiently generate node embeddings for previously unseen data. Instead of training individual embeddings for each node, we learn a function that generates embeddings by sampling and aggregating features from a node's local neighborhood. Our algorithm outperforms strong baselines on three inductive node-classification benchmarks: we classify the category of unseen nodes in evolving information graphs based on citation and Reddit post data, and we show that our algorithm generalizes to completely unseen graphs using a multi-graph dataset of protein-protein interactions.

Molecule generation with desired properties has grown immensely in popularity by disruptively changing the way scientists design molecular structures and providing support for chemical and materials design. However, despite the promising outcome, previous machine learning-based deep generative models suffer from a reliance on complex, task-specific fine-tuning, limited dimensional latent spaces, or the quality of expert rules. In this work, we propose MolGen, a pre-trained molecular language model that effectively learns and shares knowledge across multiple generation tasks and domains. Specifically, we pre-train MolGen with the chemical language SELFIES on more than 100 million unlabelled molecules. We further propose multi-task molecular prefix tuning across several molecular generation tasks and different molecular domains (synthetic & natural products) with a self-feedback mechanism. Extensive experiments show that MolGen can obtain superior performances on well-known molecular generation benchmark datasets. The further analysis illustrates that MolGen can accurately capture the distribution of molecules, implicitly learn their structural characteristics, and efficiently explore the chemical space with the guidance of multi-task molecular prefix tuning. Codes, datasets, and the pre-trained model will be available in https://github.com/zjunlp/MolGen.

There is increasing adoption of artificial intelligence in drug discovery. However, existing studies use machine learning to mainly utilize the chemical structures of molecules but ignore the vast textual knowledge available in chemistry. Incorporating textual knowledge enables us to realize new drug design objectives, adapt to text-based instructions and predict complex biological activities. Here we present a multi-modal molecule structure-text model, MoleculeSTM, by jointly learning molecules' chemical structures and textual descriptions via a contrastive learning strategy. To train MoleculeSTM, we construct a large multi-modal dataset, namely, PubChemSTM, with over 280,000 chemical structure-text pairs. To demonstrate the effectiveness and utility of MoleculeSTM, we design two challenging zero-shot tasks based on text instructions, including structure-text retrieval and molecule editing. MoleculeSTM has two main properties: open vocabulary and compositionality via natural language. In experiments, MoleculeSTM obtains the state-of-the-art generalization ability to novel biochemical concepts across various benchmarks.

The binding between proteins and ligands plays a crucial role in the realm of drug discovery. Previous deep learning approaches have shown promising results over traditional computationally intensive methods, but resulting in poor generalization due to limited supervised data. In this paper, we propose to learn protein-ligand binding representation in a self-supervised learning manner. Different from existing pre-training approaches which treat proteins and ligands individually, we emphasize to discern the intricate binding patterns from fine-grained interactions. Specifically, this self-supervised learning problem is formulated as a prediction of the conclusive binding complex structure given a pocket and ligand with a Transformer based interaction module, which naturally emulates the binding process. To ensure the representation of rich binding information, we introduce two pre-training tasks, i.e.~atomic pairwise distance map prediction and mask ligand reconstruction, which comprehensively model the fine-grained interactions from both structure and feature space. Extensive experiments have demonstrated the superiority of our method across various binding tasks, including protein-ligand affinity prediction, virtual screening and protein-ligand docking.

Recent advances in machine learning have made significant contributions to drug discovery. Deep neural networks in particular have been demonstrated to provide significant boosts in predictive power when inferring the properties and activities of small-molecule compounds. However, the applicability of these techniques has been limited by the requirement for large amounts of training data. In this work, we demonstrate how one-shot learning can be used to significantly lower the amounts of data required to make meaningful predictions in drug discovery applications. We introduce a new architecture, the residual LSTM embedding, that, when combined with graph convolutional neural networks, significantly improves the ability to learn meaningful distance metrics over small-molecules. We open source all models introduced in this work as part of DeepChem, an open-source framework for deep-learning in drug discovery.

In drug-discovery-related tasks such as virtual screening, machine learning is emerging as a promising way to predict molecular properties. Conventionally, molecular fingerprints (numerical representations of molecules) are calculated through rule-based algorithms that map molecules to a sparse discrete space. However, these algorithms perform poorly for shallow prediction models or small datasets. To address this issue, we present SMILES Transformer. Inspired by Transformer and pre-trained language models from natural language processing, SMILES Transformer learns molecular fingerprints through unsupervised pre-training of the sequence-to-sequence language model using a huge corpus of SMILES, a text representation system for molecules. We performed benchmarks on 10 datasets against existing fingerprints and graph-based methods and demonstrated the superiority of the proposed algorithms in small-data settings where pre-training facilitated good generalization. Moreover, we define a novel metric to concurrently measure model accuracy and data efficiency.

Graph neural networks (GNNs) have been used extensively for addressing problems in drug design and discovery. Both ligand and target molecules are represented as graphs with node and edge features encoding information about atomic elements and bonds respectively. Although existing deep learning models perform remarkably well at predicting physicochemical properties and binding affinities, the generation of new molecules with optimized properties remains challenging. Inherently, most GNNs perform poorly in whole-graph representation due to the limitations of the message-passing paradigm. Furthermore, step-by-step graph generation frameworks that use reinforcement learning or other sequential processing can be slow and result in a high proportion of invalid molecules with substantial post-processing needed in order to satisfy the principles of stoichiometry. To address these issues, we propose a representation-first approach to molecular graph generation. We guide the latent representation of an autoencoder by capturing graph structure information with the geometric scattering transform and apply penalties that structure the representation also by molecular properties. We show that this highly structured latent space can be directly used for molecular graph generation by the use of a GAN. We demonstrate that our architecture learns meaningful representations of drug datasets and provides a platform for goal-directed drug synthesis.

Transformer-based deep neural networks have revolutionized the field of molecular-related prediction tasks by treating molecules as symbolic sequences. These models have been successfully applied in various organic chemical applications by pretraining them with extensive compound libraries and subsequently fine-tuning them with smaller in-house datasets for specific tasks. However, many conventional methods primarily focus on single molecules, with limited exploration of pretraining for reactions involving multiple molecules. In this paper, we propose ReactionT5, a novel model that leverages pretraining on the Open Reaction Database (ORD), a publicly available large-scale resource. We further fine-tune this model for yield prediction and product prediction tasks, demonstrating its impressive performance even with limited fine-tuning data compared to traditional models. The pre-trained ReactionT5 model is publicly accessible on the Hugging Face platform.

Predicting ATP-Protein Binding sites in genes is of great significance in the field of Biology and Medicine. The majority of research in this field has been conducted through time- and resource-intensive 'wet experiments' in laboratories. Over the years, researchers have been investigating computational methods computational methods to accomplish the same goals, utilising the strength of advanced Deep Learning and NLP algorithms. In this paper, we propose to develop methods to classify ATP-Protein binding sites. We conducted various experiments mainly using PSSMs and several word embeddings as features. We used 2D CNNs and LightGBM classifiers as our chief Deep Learning Algorithms. The MP3Vec and BERT models have also been subjected to testing in our study. The outcomes of our experiments demonstrated improvement over the state-of-the-art benchmarks.

As a fundamental task in computational chemistry, retrosynthesis prediction aims to identify a set of reactants to synthesize a target molecule. Existing template-free approaches only consider the graph structures of the target molecule, which often cannot generalize well to rare reaction types and large molecules. Here, we propose T-Rex, a text-assisted retrosynthesis prediction approach that exploits pre-trained text language models, such as ChatGPT, to assist the generation of reactants. T-Rex first exploits ChatGPT to generate a description for the target molecule and rank candidate reaction centers based both the description and the molecular graph. It then re-ranks these candidates by querying the descriptions for each reactants and examines which group of reactants can best synthesize the target molecule. We observed that T-Rex substantially outperformed graph-based state-of-the-art approaches on two datasets, indicating the effectiveness of considering text information. We further found that T-Rex outperformed the variant that only use ChatGPT-based description without the re-ranking step, demonstrate how our framework outperformed a straightforward integration of ChatGPT and graph information. Collectively, we show that text generated by pre-trained language models can substantially improve retrosynthesis prediction, opening up new avenues for exploiting ChatGPT to advance computational chemistry. And the codes can be found at https://github.com/lauyikfung/T-Rex.

Foundation models applied to bio-molecular space hold promise to accelerate drug discovery. Molecular representation is key to building such models. Previous works have typically focused on a single representation or view of the molecules. Here, we develop a multi-view foundation model approach, that integrates molecular views of graph, image and text. Single-view foundation models are each pre-trained on a dataset of up to 200M molecules and then aggregated into combined representations. Our multi-view model is validated on a diverse set of 18 tasks, encompassing ligand-protein binding, molecular solubility, metabolism and toxicity. We show that the multi-view models perform robustly and are able to balance the strengths and weaknesses of specific views. We then apply this model to screen compounds against a large (>100 targets) set of G Protein-Coupled receptors (GPCRs). From this library of targets, we identify 33 that are related to Alzheimer's disease. On this subset, we employ our model to identify strong binders, which are validated through structure-based modeling and identification of key binding motifs.

Learnable embedding vector is one of the most important applications in machine learning, and is widely used in various database-related domains. However, the high dimensionality of sparse data in recommendation tasks and the huge volume of corpus in retrieval-related tasks lead to a large memory consumption of the embedding table, which poses a great challenge to the training and deployment of models. Recent research has proposed various methods to compress the embeddings at the cost of a slight decrease in model quality or the introduction of other overheads. Nevertheless, the relative performance of these methods remains unclear. Existing experimental comparisons only cover a subset of these methods and focus on limited metrics. In this paper, we perform a comprehensive comparative analysis and experimental evaluation of embedding compression. We introduce a new taxonomy that categorizes these techniques based on their characteristics and methodologies, and further develop a modular benchmarking framework that integrates 14 representative methods. Under a uniform test environment, our benchmark fairly evaluates each approach, presents their strengths and weaknesses under different memory budgets, and recommends the best method based on the use case. In addition to providing useful guidelines, our study also uncovers the limitations of current methods and suggests potential directions for future research.

Accumulated clinical studies show that microbes living in humans interact closely with human hosts, and get involved in modulating drug efficacy and drug toxicity. Microbes have become novel targets for the development of antibacterial agents. Therefore, screening of microbe-drug associations can benefit greatly drug research and development. With the increase of microbial genomic and pharmacological datasets, we are greatly motivated to develop an effective computational method to identify new microbe-drug associations. In this paper, we proposed a novel method, Graph2MDA, to predict microbe-drug associations by using variational graph autoencoder (VGAE). We constructed multi-modal attributed graphs based on multiple features of microbes and drugs, such as molecular structures, microbe genetic sequences, and function annotations. Taking as input the multi-modal attribute graphs, VGAE was trained to learn the informative and interpretable latent representations of each node and the whole graph, and then a deep neural network classifier was used to predict microbe-drug associations. The hyperparameter analysis and model ablation studies showed the sensitivity and robustness of our model. We evaluated our method on three independent datasets and the experimental results showed that our proposed method outperformed six existing state-of-the-art methods. We also explored the meaningness of the learned latent representations of drugs and found that the drugs show obvious clustering patterns that are significantly consistent with drug ATC classification. Moreover, we conducted case studies on two microbes and two drugs and found 75\%-95\% predicted associations have been reported in PubMed literature. Our extensive performance evaluations validated the effectiveness of our proposed method.\

Motivation: Ab initio protein docking represents a major challenge for optimizing a noisy and costly "black box"-like function in a high-dimensional space. Despite progress in this field, there is no docking method available for rigorous uncertainty quantification (UQ) of its solution quality (e.g. interface RMSD or iRMSD). Results: We introduce a novel algorithm, Bayesian Active Learning (BAL), for optimization and UQ of such black-box functions and flexible protein docking. BAL directly models the posterior distribution of the global optimum (or native structures for protein docking) with active sampling and posterior estimation iteratively feeding each other. Furthermore, we use complex normal modes to represent a homogeneous Euclidean conformation space suitable for high-dimension optimization and construct funnel-like energy models for encounter complexes. Over a protein docking benchmark set and a CAPRI set including homology docking, we establish that BAL significantly improve against both starting points by rigid docking and refinements by particle swarm optimization, providing for one third targets a top-3 near-native prediction. BAL also generates tight confidence intervals with half range around 25% of iRMSD and confidence level at 85%. Its estimated probability of a prediction being native or not achieves binary classification AUROC at 0.93 and AUPRC over 0.60 (compared to 0.14 by chance); and also found to help ranking predictions. To the best of our knowledge, this study represents the first uncertainty quantification solution for protein docking, with theoretical rigor and comprehensive assessment. Source codes are available at https://github.com/Shen-Lab/BAL.

Recent years have seen the advent of molecular simulation datasets that are orders of magnitude larger and more diverse. These new datasets differ substantially in four aspects of complexity: 1. Chemical diversity (number of different elements), 2. system size (number of atoms per sample), 3. dataset size (number of data samples), and 4. domain shift (similarity of the training and test set). Despite these large differences, benchmarks on small and narrow datasets remain the predominant method of demonstrating progress in graph neural networks (GNNs) for molecular simulation, likely due to cheaper training compute requirements. This raises the question -- does GNN progress on small and narrow datasets translate to these more complex datasets? This work investigates this question by first developing the GemNet-OC model based on the large Open Catalyst 2020 (OC20) dataset. GemNet-OC outperforms the previous state-of-the-art on OC20 by 16% while reducing training time by a factor of 10. We then compare the impact of 18 model components and hyperparameter choices on performance in multiple datasets. We find that the resulting model would be drastically different depending on the dataset used for making model choices. To isolate the source of this discrepancy we study six subsets of the OC20 dataset that individually test each of the above-mentioned four dataset aspects. We find that results on the OC-2M subset correlate well with the full OC20 dataset while being substantially cheaper to train on. Our findings challenge the common practice of developing GNNs solely on small datasets, but highlight ways of achieving fast development cycles and generalizable results via moderately-sized, representative datasets such as OC-2M and efficient models such as GemNet-OC. Our code and pretrained model weights are open-sourced.

The effects of ligand binding on protein structures and their in vivo functions carry numerous implications for modern biomedical research and biotechnology development efforts such as drug discovery. Although several deep learning (DL) methods and benchmarks designed for protein-ligand docking have recently been introduced, to date no prior works have systematically studied the behavior of the latest docking and structure prediction methods within the broadly applicable context of (1) using predicted (apo) protein structures for docking (e.g., for applicability to new proteins); (2) binding multiple (cofactor) ligands concurrently to a given target protein (e.g., for enzyme design); and (3) having no prior knowledge of binding pockets (e.g., for generalization to unknown pockets). To enable a deeper understanding of docking methods' real-world utility, we introduce PoseBench, the first comprehensive benchmark for broadly applicable protein-ligand docking. PoseBench enables researchers to rigorously and systematically evaluate DL methods for apo-to-holo protein-ligand docking and protein-ligand structure prediction using both primary ligand and multi-ligand benchmark datasets, the latter of which we introduce for the first time to the DL community. Empirically, using PoseBench, we find that (1) DL co-folding methods generally outperform comparable conventional and DL docking baselines, yet popular methods such as AlphaFold 3 are still challenged by prediction targets with novel protein sequences; (2) certain DL co-folding methods are highly sensitive to their input multiple sequence alignments, while others are not; and (3) DL methods struggle to strike a balance between structural accuracy and chemical specificity when predicting novel or multi-ligand protein targets. Code, data, tutorials, and benchmark results are available at https://github.com/BioinfoMachineLearning/PoseBench.

Activity and property prediction models are the central workhorses in drug discovery and materials sciences, but currently they have to be trained or fine-tuned for new tasks. Without training or fine-tuning, scientific language models could be used for such low-data tasks through their announced zero- and few-shot capabilities. However, their predictive quality at activity prediction is lacking. In this work, we envision a novel type of activity prediction model that is able to adapt to new prediction tasks at inference time, via understanding textual information describing the task. To this end, we propose a new architecture with separate modules for chemical and natural language inputs, and a contrastive pre-training objective on data from large biochemical databases. In extensive experiments, we show that our method CLAMP yields improved predictive performance on few-shot learning benchmarks and zero-shot problems in drug discovery. We attribute the advances of our method to the modularized architecture and to our pre-training objective.

Denoising diffusion models have shown great potential in multiple research areas. Existing diffusion-based generative methods on de novo 3D molecule generation face two major challenges. Since majority heavy atoms in molecules allow connections to multiple atoms through single bonds, solely using pair-wise distance to model molecule geometries is insufficient. Therefore, the first one involves proposing an effective neural network as the denoising kernel that is capable to capture complex multi-body interatomic relationships and learn high-quality features. Due to the discrete nature of graphs, mainstream diffusion-based methods for molecules heavily rely on predefined rules and generate edges in an indirect manner. The second challenge involves accommodating molecule generation to diffusion and accurately predicting the existence of bonds. In our research, we view the iterative way of updating molecule conformations in diffusion process is consistent with molecular dynamics and introduce a novel molecule generation method named Geometric-Facilitated Molecular Diffusion (GFMDiff). For the first challenge, we introduce a Dual-Track Transformer Network (DTN) to fully excevate global spatial relationships and learn high quality representations which contribute to accurate predictions of features and geometries. As for the second challenge, we design Geometric-Facilitated Loss (GFLoss) which intervenes the formation of bonds during the training period, instead of directly embedding edges into the latent space. Comprehensive experiments on current benchmarks demonstrate the superiority of GFMDiff.

Deep generative models (DGMs) have been widely developed for graph data. However, much less investigation has been carried out on understanding the latent space of such pretrained graph DGMs. These understandings possess the potential to provide constructive guidelines for crucial tasks, such as graph controllable generation. Thus in this work, we are interested in studying this problem and propose GraphCG, a method for the unsupervised discovery of steerable factors in the latent space of pretrained graph DGMs. We first examine the representation space of three pretrained graph DGMs with six disentanglement metrics, and we observe that the pretrained representation space is entangled. Motivated by this observation, GraphCG learns the steerable factors via maximizing the mutual information between semantic-rich directions, where the controlled graph moving along the same direction will share the same steerable factors. We quantitatively verify that GraphCG outperforms four competitive baselines on two graph DGMs pretrained on two molecule datasets. Additionally, we qualitatively illustrate seven steerable factors learned by GraphCG on five pretrained DGMs over five graph datasets, including two for molecules and three for point clouds.

Persistent homology, a technique from computational topology, has recently shown strong empirical performance in the context of graph classification. Being able to capture long range graph properties via higher-order topological features, such as cycles of arbitrary length, in combination with multi-scale topological descriptors, has improved predictive performance for data sets with prominent topological structures, such as molecules. At the same time, the theoretical properties of persistent homology have not been formally assessed in this context. This paper intends to bridge the gap between computational topology and graph machine learning by providing a brief introduction to persistent homology in the context of graphs, as well as a theoretical discussion and empirical analysis of its expressivity for graph learning tasks.

Catalyst discovery and optimization is key to solving many societal and energy challenges including solar fuels synthesis, long-term energy storage, and renewable fertilizer production. Despite considerable effort by the catalysis community to apply machine learning models to the computational catalyst discovery process, it remains an open challenge to build models that can generalize across both elemental compositions of surfaces and adsorbate identity/configurations, perhaps because datasets have been smaller in catalysis than related fields. To address this we developed the OC20 dataset, consisting of 1,281,040 Density Functional Theory (DFT) relaxations (~264,890,000 single point evaluations) across a wide swath of materials, surfaces, and adsorbates (nitrogen, carbon, and oxygen chemistries). We supplemented this dataset with randomly perturbed structures, short timescale molecular dynamics, and electronic structure analyses. The dataset comprises three central tasks indicative of day-to-day catalyst modeling and comes with pre-defined train/validation/test splits to facilitate direct comparisons with future model development efforts. We applied three state-of-the-art graph neural network models (CGCNN, SchNet, Dimenet++) to each of these tasks as baseline demonstrations for the community to build on. In almost every task, no upper limit on model size was identified, suggesting that even larger models are likely to improve on initial results. The dataset and baseline models are both provided as open resources, as well as a public leader board to encourage community contributions to solve these important tasks.

Molecule discovery is a pivotal research field, impacting everything from the medicines we take to the materials we use. Recently, Large Language Models (LLMs) have been widely adopted in molecule understanding and generation, yet the alignments between molecules and their corresponding captions remain a significant challenge. Previous endeavours often treat the molecule as a general SMILES string or molecular graph, neglecting the fine-grained alignments between the molecular sub-structures and the descriptive textual phrases, which are crucial for accurate and explainable predictions. In this case, we introduce MolReFlect, a novel teacher-student framework designed to contextually perform the molecule-caption alignments in a fine-grained way. Our approach initially leverages a larger teacher LLM to label the detailed alignments by directly extracting critical phrases from molecule captions or SMILES strings and implying them to corresponding sub-structures or characteristics. To refine these alignments, we propose In-Context Selective Reflection, which retrieves previous extraction results as context examples for teacher LLM to reflect and lets a smaller student LLM select from in-context reflection and previous extraction results. Finally, we enhance the learning process of the student LLM through Chain-of-Thought In-Context Molecule Tuning, integrating the fine-grained alignments and the reasoning processes within the Chain-of-Thought format. Our experimental results demonstrate that MolReFlect enables LLMs like Mistral-7B to significantly outperform the previous baselines, achieving SOTA performance on the ChEBI-20 dataset. This advancement not only enhances the generative capabilities of LLMs in the molecule-caption translation task, but also contributes to a more explainable framework.

While various models and computational tools have been proposed for structure and property analysis of molecules, generating molecules that conform to all desired structures and properties remains a challenge. Here, we introduce a multi-constraint molecular generation large language model, TSMMG, which, akin to a student, incorporates knowledge from various small models and tools, namely, the 'teachers'. To train TSMMG, we construct a large set of text-molecule pairs by extracting molecular knowledge from these 'teachers', enabling it to generate novel molecules that conform to the descriptions through various text prompts. We experimentally show that TSMMG remarkably performs in generating molecules meeting complex, natural language-described property requirements across two-, three-, and four-constraint tasks, with an average molecular validity of over 99% and success ratio of 82.58%, 68.03%, and 67.48%, respectively. The model also exhibits adaptability through zero-shot testing, creating molecules that satisfy combinations of properties that have not been encountered. It can comprehend text inputs with various language styles, extending beyond the confines of outlined prompts, as confirmed through empirical validation. Additionally, the knowledge distillation feature of TSMMG contributes to the continuous enhancement of small models, while the innovative approach to dataset construction effectively addresses the issues of data scarcity and quality, which positions TSMMG as a promising tool in the domains of drug discovery and materials science.

Drug discovery is a complex process that involves multiple scenarios and stages, such as fragment-constrained molecule generation, hit generation and lead optimization. However, existing molecular generative models can only tackle one or two of these scenarios and lack the flexibility to address various aspects of the drug discovery pipeline. In this paper, we present Generalist Molecular generative model (GenMol), a versatile framework that addresses these limitations by applying discrete diffusion to the Sequential Attachment-based Fragment Embedding (SAFE) molecular representation. GenMol generates SAFE sequences through non-autoregressive bidirectional parallel decoding, thereby allowing utilization of a molecular context that does not rely on the specific token ordering and enhanced computational efficiency. Moreover, under the discrete diffusion framework, we introduce fragment remasking, a strategy that optimizes molecules by replacing fragments with masked tokens and regenerating them, enabling effective exploration of chemical space. GenMol significantly outperforms the previous GPT-based model trained on SAFE representations in de novo generation and fragment-constrained generation, and achieves state-of-the-art performance in goal-directed hit generation and lead optimization. These experimental results demonstrate that GenMol can tackle a wide range of drug discovery tasks, providing a unified and versatile approach for molecular design.

Machine Learning Force Fields (MLFFs) are a promising alternative to expensive ab initio quantum mechanical molecular simulations. Given the diversity of chemical spaces that are of interest and the cost of generating new data, it is important to understand how MLFFs generalize beyond their training distributions. In order to characterize and better understand distribution shifts in MLFFs, we conduct diagnostic experiments on chemical datasets, revealing common shifts that pose significant challenges, even for large foundation models trained on extensive data. Based on these observations, we hypothesize that current supervised training methods inadequately regularize MLFFs, resulting in overfitting and learning poor representations of out-of-distribution systems. We then propose two new methods as initial steps for mitigating distribution shifts for MLFFs. Our methods focus on test-time refinement strategies that incur minimal computational cost and do not use expensive ab initio reference labels. The first strategy, based on spectral graph theory, modifies the edges of test graphs to align with graph structures seen during training. Our second strategy improves representations for out-of-distribution systems at test-time by taking gradient steps using an auxiliary objective, such as a cheap physical prior. Our test-time refinement strategies significantly reduce errors on out-of-distribution systems, suggesting that MLFFs are capable of and can move towards modeling diverse chemical spaces, but are not being effectively trained to do so. Our experiments establish clear benchmarks for evaluating the generalization capabilities of the next generation of MLFFs. Our code is available at https://tkreiman.github.io/projects/mlff_distribution_shifts/.

We report a flexible language-model based deep learning strategy, applied here to solve complex forward and inverse problems in protein modeling, based on an attention neural network that integrates transformer and graph convolutional architectures in a causal multi-headed graph mechanism, to realize a generative pretrained model. The model is applied to predict secondary structure content (per-residue level and overall content), protein solubility, and sequencing tasks. Further trained on inverse tasks, the model is rendered capable of designing proteins with these properties as target features. The model is formulated as a general framework, completely prompt-based, and can be adapted for a variety of downstream tasks. We find that adding additional tasks yields emergent synergies that the model exploits in improving overall performance, beyond what would be possible by training a model on each dataset alone. Case studies are presented to validate the method, yielding protein designs specifically focused on structural proteins, but also exploring the applicability in the design of soluble, antimicrobial biomaterials. While our model is trained to ultimately perform 8 distinct tasks, with available datasets it can be extended to solve additional problems. In a broader sense, this work illustrates a form of multiscale modeling that relates a set of ultimate building blocks (here, byte-level utf8 characters) to complex output. This materiomic scheme captures complex emergent relationships between universal building block and resulting properties via a synergizing learning capacity to express a set of potentialities embedded in the knowledge used in training, via the interplay of universality and diversity.

Machine learning techniques are essential tools to compute efficient, yet accurate, force fields for atomistic simulations. This approach has recently been extended to incorporate quantum computational methods, making use of variational quantum learning models to predict potential energy surfaces and atomic forces from ab initio training data. However, the trainability and scalability of such models are still limited, due to both theoretical and practical barriers. Inspired by recent developments in geometric classical and quantum machine learning, here we design quantum neural networks that explicitly incorporate, as a data-inspired prior, an extensive set of physically relevant symmetries. We find that our invariant quantum learning models outperform their more generic counterparts on individual molecules of growing complexity. Furthermore, we study a water dimer as a minimal example of a system with multiple components, showcasing the versatility of our proposed approach and opening the way towards larger simulations. Our results suggest that molecular force fields generation can significantly profit from leveraging the framework of geometric quantum machine learning, and that chemical systems represent, in fact, an interesting and rich playground for the development and application of advanced quantum machine learning tools.

We introduce SynFormer, a generative modeling framework designed to efficiently explore and navigate synthesizable chemical space. Unlike traditional molecular generation approaches, we generate synthetic pathways for molecules to ensure that designs are synthetically tractable. By incorporating a scalable transformer architecture and a diffusion module for building block selection, SynFormer surpasses existing models in synthesizable molecular design. We demonstrate SynFormer's effectiveness in two key applications: (1) local chemical space exploration, where the model generates synthesizable analogs of a reference molecule, and (2) global chemical space exploration, where the model aims to identify optimal molecules according to a black-box property prediction oracle. Additionally, we demonstrate the scalability of our approach via the improvement in performance as more computational resources become available. With our code and trained models openly available, we hope that SynFormer will find use across applications in drug discovery and materials science.

Building generalist models has recently demonstrated remarkable capabilities in diverse scientific domains. Within the realm of molecular learning, several studies have explored unifying diverse tasks across diverse domains. However, negative conflicts and interference between molecules and knowledge from different domain may have a worse impact in threefold. First, conflicting molecular representations can lead to optimization difficulties for the models. Second, mixing and scaling up training data across diverse tasks is inherently challenging. Third, the computational cost of refined pretraining is prohibitively high. To address these limitations, this paper presents Omni-Mol, a scalable and unified LLM-based framework for direct instruction tuning. Omni-Mol builds on three key components to tackles conflicts: (1) a unified encoding mechanism for any task input; (2) an active-learning-driven data selection strategy that significantly reduces dataset size; (3) a novel design of the adaptive gradient stabilization module and anchor-and-reconcile MoE framework that ensures stable convergence. Experimentally, Omni-Mol achieves state-of-the-art performance across 15 molecular tasks, demonstrates the presence of scaling laws in the molecular domain, and is supported by extensive ablation studies and analyses validating the effectiveness of its design. The code and weights of the powerful AI-driven chemistry generalist are open-sourced at: https://anonymous.4open.science/r/Omni-Mol-8EDB.

Webly supervised learning has attracted increasing attention for its effectiveness in exploring publicly accessible data at scale without manual annotation. However, most existing methods of learning with web datasets are faced with challenges from label noise, and they have limited assumptions on clean samples under various noise. For instance, web images retrieved with queries of tiger cat (a cat species) and drumstick (a musical instrument) are almost dominated by images of tigers and chickens, which exacerbates the challenge of fine-grained visual concept learning. In this case, exploiting both web images and their associated texts is a requisite solution to combat real-world noise. In this paper, we propose Cross-modality Aligned Prototypes (CAPro), a unified prototypical contrastive learning framework to learn visual representations with correct semantics. For one thing, we leverage textual prototypes, which stem from the distinct concept definition of classes, to select clean images by text matching and thus disambiguate the formation of visual prototypes. For another, to handle missing and mismatched noisy texts, we resort to the visual feature space to complete and enhance individual texts and thereafter improve text matching. Such semantically aligned visual prototypes are further polished up with high-quality samples, and engaged in both cluster regularization and noise removal. Besides, we propose collective bootstrapping to encourage smoother and wiser label reference from appearance-similar instances in a manner of dictionary look-up. Extensive experiments on WebVision1k and NUS-WIDE (Web) demonstrate that CAPro well handles realistic noise under both single-label and multi-label scenarios. CAPro achieves new state-of-the-art performance and exhibits robustness to open-set recognition. Codes are available at https://github.com/yuleiqin/capro.

Large Language Models (LLMs) stand at the forefront of a number of Natural Language Processing (NLP) tasks. Despite the widespread adoption of LLMs in NLP, much of their potential in broader fields remains largely unexplored, and significant limitations persist in their design and implementation. Notably, LLMs struggle with structured data, such as graphs, and often falter when tasked with answering domain-specific questions requiring deep expertise, such as those in biology and chemistry. In this paper, we explore a fundamental question: Can LLMs effectively handle molecule prediction tasks? Rather than pursuing top-tier performance, our goal is to assess how LLMs can contribute to diverse molecule tasks. We identify several classification and regression prediction tasks across six standard molecule datasets. Subsequently, we carefully design a set of prompts to query LLMs on these tasks and compare their performance with existing Machine Learning (ML) models, which include text-based models and those specifically designed for analysing the geometric structure of molecules. Our investigation reveals several key insights: Firstly, LLMs generally lag behind ML models in achieving competitive performance on molecule tasks, particularly when compared to models adept at capturing the geometric structure of molecules, highlighting the constrained ability of LLMs to comprehend graph data. Secondly, LLMs show promise in enhancing the performance of ML models when used collaboratively. Lastly, we engage in a discourse regarding the challenges and promising avenues to harness LLMs for molecule prediction tasks. The code and models are available at https://github.com/zhiqiangzhongddu/LLMaMol.

Retrosynthetic planning aims to devise a complete multi-step synthetic route from starting materials to a target molecule. Current strategies use a decoupled approach of single-step retrosynthesis models and search algorithms, taking only the product as the input to predict the reactants for each planning step and ignoring valuable context information along the synthetic route. In this work, we propose a novel framework that utilizes context information for improved retrosynthetic planning. We view synthetic routes as reaction graphs and propose to incorporate context through three principled steps: encode molecules into embeddings, aggregate information over routes, and readout to predict reactants. Our approach is the first attempt to utilize in-context learning for retrosynthesis prediction in retrosynthetic planning. The entire framework can be efficiently optimized in an end-to-end fashion and produce more practical and accurate predictions. Comprehensive experiments demonstrate that by fusing in the context information over routes, our model significantly improves the performance of retrosynthetic planning over baselines that are not context-aware, especially for long synthetic routes. Code is available at https://github.com/SongtaoLiu0823/FusionRetro.

Learning effective protein representations is critical in a variety of tasks in biology such as predicting protein function or structure. Existing approaches usually pretrain protein language models on a large number of unlabeled amino acid sequences and then finetune the models with some labeled data in downstream tasks. Despite the effectiveness of sequence-based approaches, the power of pretraining on known protein structures, which are available in smaller numbers only, has not been explored for protein property prediction, though protein structures are known to be determinants of protein function. In this paper, we propose to pretrain protein representations according to their 3D structures. We first present a simple yet effective encoder to learn the geometric features of a protein. We pretrain the protein graph encoder by leveraging multiview contrastive learning and different self-prediction tasks. Experimental results on both function prediction and fold classification tasks show that our proposed pretraining methods outperform or are on par with the state-of-the-art sequence-based methods, while using much less pretraining data. Our implementation is available at https://github.com/DeepGraphLearning/GearNet.

The rapid advancement of large-scale vision-language models has showcased remarkable capabilities across various tasks. However, the lack of extensive and high-quality image-text data in medicine has greatly hindered the development of large-scale medical vision-language models. In this work, we present a diagnosis-guided bootstrapping strategy that exploits both image and label information to construct vision-language datasets. Based on the constructed dataset, we developed MedDr, a generalist foundation model for healthcare capable of handling diverse medical data modalities, including radiology, pathology, dermatology, retinography, and endoscopy. Moreover, during inference, we propose a simple but effective retrieval-augmented medical diagnosis strategy, which enhances the model's generalization ability. Extensive experiments on visual question answering, medical report generation, and medical image diagnosis demonstrate the superiority of our method.

The success of drug discovery and development relies on the precise prediction of molecular activities and properties. While in silico molecular property prediction has shown remarkable potential, its use has been limited so far to assays for which large amounts of data are available. In this study, we use a fine-tuned large language model to integrate biological assays based on their textual information, coupled with Barlow Twins, a Siamese neural network using a novel self-supervised learning approach. This architecture uses both assay information and molecular fingerprints to extract the true molecular information. TwinBooster enables the prediction of properties of unseen bioassays and molecules by providing state-of-the-art zero-shot learning tasks. Remarkably, our artificial intelligence pipeline shows excellent performance on the FS-Mol benchmark. This breakthrough demonstrates the application of deep learning to critical property prediction tasks where data is typically scarce. By accelerating the early identification of active molecules in drug discovery and development, this method has the potential to help streamline the identification of novel therapeutics.

Recent research in representation learning utilizes large databases of proteins or molecules to acquire knowledge of drug and protein structures through unsupervised learning techniques. These pre-trained representations have proven to significantly enhance the accuracy of subsequent tasks, such as predicting the affinity between drugs and target proteins. In this study, we demonstrate that by incorporating knowledge graphs from diverse sources and modalities into the sequences or SMILES representation, we can further enrich the representation and achieve state-of-the-art results on established benchmark datasets. We provide preprocessed and integrated data obtained from 7 public sources, which encompass over 30M triples. Additionally, we make available the pre-trained models based on this data, along with the reported outcomes of their performance on three widely-used benchmark datasets for drug-target binding affinity prediction found in the Therapeutic Data Commons (TDC) benchmarks. Additionally, we make the source code for training models on benchmark datasets publicly available. Our objective in releasing these pre-trained models, accompanied by clean data for model pretraining and benchmark results, is to encourage research in knowledge-enhanced representation learning.

Understanding protein solubility is essential for their functional applications. Computational methods for predicting protein solubility are crucial for reducing experimental costs and enhancing the efficiency and success rates of protein engineering. Existing methods either construct a supervised learning scheme on small-scale datasets with manually processed physicochemical properties, or blindly apply pre-trained protein language models to extract amino acid interaction information. The scale and quality of available training datasets leave significant room for improvement in terms of accuracy and generalization. To address these research gaps, we propose \sol, a novel deep learning method that combines pre-training and fine-tuning schemes for protein solubility prediction. ProtSolM integrates information from multiple dimensions, including physicochemical properties, amino acid sequences, and protein backbone structures. Our model is trained using \data, the largest solubility dataset that we have constructed. PDBSol includes over 60,000 protein sequences and structures. We provide a comprehensive leaderboard of existing statistical learning and deep learning methods on independent datasets with computational and experimental labels. ProtSolM achieved state-of-the-art performance across various evaluation metrics, demonstrating its potential to significantly advance the accuracy of protein solubility prediction.

Molecular docking is a key computational tool utilized to predict the binding conformations of small molecules to protein targets, which is fundamental in the design of novel drugs. Despite recent advancements in geometric deep learning-based approaches leading to improvements in blind docking efficiency, these methods have encountered notable challenges, such as limited generalization performance on unseen proteins, the inability to concurrently address the settings of blind docking and site-specific docking, and the frequent occurrence of physical implausibilities such as inter-molecular steric clash. In this study, we introduce DeltaDock, a robust and versatile framework designed for efficient molecular docking to overcome these challenges. DeltaDock operates in a two-step process: rapid initial complex structures sampling followed by multi-scale iterative refinement of the initial structures. In the initial stage, to sample accurate structures with high efficiency, we develop a ligand-dependent binding site prediction model founded on large protein models and graph neural networks. This model is then paired with GPU-accelerated sampling algorithms. The sampled structures are updated using a multi-scale iterative refinement module that captures both protein-ligand atom-atom interactions and residue-atom interactions in the following stage. Distinct from previous geometric deep learning methods that are conditioned on the blind docking setting, DeltaDock demonstrates superior performance in both blind docking and site-specific docking settings. Comprehensive experimental results reveal that DeltaDock consistently surpasses baseline methods in terms of docking accuracy. Furthermore, it displays remarkable generalization capabilities and proficiency for predicting physically valid structures, thereby attesting to its robustness and reliability in various scenarios.

The rapid expansion of genomic sequence data calls for new methods to achieve robust sequence representations. Existing techniques often neglect intricate structural details, emphasizing mainly contextual information. To address this, we developed k-mer embeddings that merge contextual and structural string information by enhancing De Bruijn graphs with structural similarity connections. Subsequently, we crafted a self-supervised method based on Contrastive Learning that employs a heterogeneous Graph Convolutional Network encoder and constructs positive pairs based on node similarities. Our embeddings consistently outperform prior techniques for Edit Distance Approximation and Closest String Retrieval tasks.

Graph Neural Networks (GNNs) have been widely adopted for drug discovery with molecular graphs. Nevertheless, current GNNs are mainly good at leveraging short-range interactions (SRI) but struggle to capture long-range interactions (LRI), both of which are crucial for determining molecular properties. To tackle this issue, we propose a method that implicitly projects all original atoms into a few Neural Atoms, which abstracts the collective information of atomic groups within a molecule. Specifically, we explicitly exchange the information among neural atoms and project them back to the atoms' representations as an enhancement. With this mechanism, neural atoms establish the communication channels among distant nodes, effectively reducing the interaction scope of arbitrary node pairs into a single hop. To provide an inspection of our method from a physical perspective, we reveal its connection with the traditional LRI calculation method, Ewald Summation. We conduct extensive experiments on three long-range graph benchmarks, covering both graph-level and link-level tasks on molecular graphs. We empirically justify that our method can be equipped with an arbitrary GNN and help to capture LRI.

Predicting gene function from its DNA sequence is a fundamental challenge in biology. Many deep learning models have been proposed to embed DNA sequences and predict their enzymatic function, leveraging information in public databases linking DNA sequences to an enzymatic function label. However, much of the scientific community's knowledge of biological function is not represented in these categorical labels, and is instead captured in unstructured text descriptions of mechanisms, reactions, and enzyme behavior. These descriptions are often captured alongside DNA sequences in biological databases, albeit in an unstructured manner. Deep learning of models predicting enzymatic function are likely to benefit from incorporating this multi-modal data encoding scientific knowledge of biological function. There is, however, no dataset designed for machine learning algorithms to leverage this multi-modal information. Here we propose a novel dataset and benchmark suite that enables the exploration and development of large multi-modal neural network models on gene DNA sequences and natural language descriptions of gene function. We present baseline performance on benchmarks for both unsupervised and supervised tasks that demonstrate the difficulty of this modeling objective, while demonstrating the potential benefit of incorporating multi-modal data types in function prediction compared to DNA sequences alone. Our dataset is at: https://hoarfrost-lab.github.io/BioTalk/.

Despite recent advancements, most computational methods for molecule optimization are constrained to single- or double-property optimization tasks and suffer from poor scalability and generalizability to novel optimization tasks. Meanwhile, Large Language Models (LLMs) demonstrate remarkable out-of-domain generalizability to novel tasks. To demonstrate LLMs' potential for molecule optimization, we introduce MoMUInstruct, the first high-quality instruction-tuning dataset specifically focused on complex multi-property molecule optimization tasks. Leveraging MoMUInstruct, we develop GeLLM^3Os, a series of instruction-tuned LLMs for molecule optimization. Extensive evaluations across 5 in-domain and 5 out-of-domain tasks demonstrate that GeLLM^3Os consistently outperform state-of-the-art baselines. GeLLM^3Os also exhibit outstanding zero-shot generalization to unseen tasks, significantly outperforming powerful closed-source LLMs. Such strong generalizability demonstrates the tremendous potential of GeLLM^3Os as foundational models for molecule optimization, thereby tackling novel optimization tasks without resource-intensive retraining. MoMUInstruct, models, and code are accessible through https://github.com/ninglab/GeLLMO.

Modeling the interaction between proteins and ligands and accurately predicting their binding structures is a critical yet challenging task in drug discovery. Recent advancements in deep learning have shown promise in addressing this challenge, with sampling-based and regression-based methods emerging as two prominent approaches. However, these methods have notable limitations. Sampling-based methods often suffer from low efficiency due to the need for generating multiple candidate structures for selection. On the other hand, regression-based methods offer fast predictions but may experience decreased accuracy. Additionally, the variation in protein sizes often requires external modules for selecting suitable binding pockets, further impacting efficiency. In this work, we propose FABind, an end-to-end model that combines pocket prediction and docking to achieve accurate and fast protein-ligand binding. FABind incorporates a unique ligand-informed pocket prediction module, which is also leveraged for docking pose estimation. The model further enhances the docking process by incrementally integrating the predicted pocket to optimize protein-ligand binding, reducing discrepancies between training and inference. Through extensive experiments on benchmark datasets, our proposed FABind demonstrates strong advantages in terms of effectiveness and efficiency compared to existing methods. Our code is available at https://github.com/QizhiPei/FABind

Topological data analysis (TDA) is an area of data science that focuses on using invariants from algebraic topology to provide multiscale shape descriptors for geometric data sets such as point clouds. One of the most important such descriptors is {\em persistent homology}, which encodes the change in shape as a filtration parameter changes; a typical parameter is the feature scale. For many data sets, it is useful to simultaneously vary multiple filtration parameters, for example feature scale and density. While the theoretical properties of single parameter persistent homology are well understood, less is known about the multiparameter case. In particular, a central question is the problem of representing multiparameter persistent homology by elements of a vector space for integration with standard machine learning algorithms. Existing approaches to this problem either ignore most of the multiparameter information to reduce to the one-parameter case or are heuristic and potentially unstable in the face of noise. In this article, we introduce a new general representation framework that leverages recent results on {\em decompositions} of multiparameter persistent homology. This framework is rich in information, fast to compute, and encompasses previous approaches. Moreover, we establish theoretical stability guarantees under this framework as well as efficient algorithms for practical computation, making this framework an applicable and versatile tool for analyzing geometric and point cloud data. We validate our stability results and algorithms with numerical experiments that demonstrate statistical convergence, prediction accuracy, and fast running times on several real data sets.

Biological processes, functions, and properties are intricately linked to the ensemble of protein conformations, rather than being solely determined by a single stable conformation. In this study, we have developed P2DFlow, a generative model based on SE(3) flow matching, to predict the structural ensembles of proteins. We specifically designed a valuable prior for the flow process and enhanced the model's ability to distinguish each intermediate state by incorporating an additional dimension to describe the ensemble data, which can reflect the physical laws governing the distribution of ensembles, so that the prior knowledge can effectively guide the generation process. When trained and evaluated on the MD datasets of ATLAS, P2DFlow outperforms other baseline models on extensive experiments, successfully capturing the observable dynamic fluctuations as evidenced in crystal structure and MD simulations. As a potential proxy agent for protein molecular simulation, the high-quality ensembles generated by P2DFlow could significantly aid in understanding protein functions across various scenarios. Code is available at https://github.com/BLEACH366/P2DFlow

Deep generative diffusion models are a promising avenue for 3D de novo molecular design in materials science and drug discovery. However, their utility is still limited by suboptimal performance on large molecular structures and limited training data. To address this gap, we explore the design space of E(3)-equivariant diffusion models, focusing on previously unexplored areas. Our extensive comparative analysis evaluates the interplay between continuous and discrete state spaces. From this investigation, we present the EQGAT-diff model, which consistently outperforms established models for the QM9 and GEOM-Drugs datasets. Significantly, EQGAT-diff takes continuous atom positions, while chemical elements and bond types are categorical and uses time-dependent loss weighting, substantially increasing training convergence, the quality of generated samples, and inference time. We also showcase that including chemically motivated additional features like hybridization states in the diffusion process enhances the validity of generated molecules. To further strengthen the applicability of diffusion models to limited training data, we investigate the transferability of EQGAT-diff trained on the large PubChem3D dataset with implicit hydrogen atoms to target different data distributions. Fine-tuning EQGAT-diff for just a few iterations shows an efficient distribution shift, further improving performance throughout data sets. Finally, we test our model on the Crossdocked data set for structure-based de novo ligand generation, underlining the importance of our findings showing state-of-the-art performance on Vina docking scores.

Methods for designing organic materials with desired properties have high potential impact across fields such as medicine, renewable energy, petrochemical engineering, and agriculture. However, using generative modeling to design substances with desired properties is difficult because candidate compounds must satisfy multiple constraints, including synthetic accessibility and other metrics that are intuitive to domain experts but challenging to quantify. We propose C5T5, a novel self-supervised pretraining method that enables transformers to make zero-shot select-and-replace edits, altering organic substances towards desired property values. C5T5 operates on IUPAC names -- a standardized molecular representation that intuitively encodes rich structural information for organic chemists but that has been largely ignored by the ML community. Our technique requires no edited molecule pairs to train and only a rough estimate of molecular properties, and it has the potential to model long-range dependencies and symmetric molecular structures more easily than graph-based methods. C5T5 also provides a powerful interface to domain experts: it grants users fine-grained control over the generative process by selecting and replacing IUPAC name fragments, which enables experts to leverage their intuitions about structure-activity relationships. We demonstrate C5T5's effectiveness on four physical properties relevant for drug discovery, showing that it learns successful and chemically intuitive strategies for altering molecules towards desired property values.

Cryo-electron microscopy (cryo-EM) is a technique for reconstructing the 3-dimensional (3D) structure of biomolecules (especially large protein complexes and molecular assemblies). As the resolution increases to the near-atomic scale, building protein structures de novo from cryo-EM maps becomes possible. Recently, recognition-based de novo building methods have shown the potential to streamline this process. However, it cannot build a complete structure due to the low signal-to-noise ratio (SNR) problem. At the same time, AlphaFold has led to a great breakthrough in predicting protein structures. This has inspired us to combine fragment recognition and structure prediction methods to build a complete structure. In this paper, we propose a new method named FFF that bridges protein structure prediction and protein structure recognition with flexible fitting. First, a multi-level recognition network is used to capture various structural features from the input 3D cryo-EM map. Next, protein structural fragments are generated using pseudo peptide vectors and a protein sequence alignment method based on these extracted features. Finally, a complete structural model is constructed using the predicted protein fragments via flexible fitting. Based on our benchmark tests, FFF outperforms the baseline methods for building complete protein structures.