However, now that a baseline accuracy has been established, future development will target rapid and systematic evolution of the force field functional form. These strategies involve identifying key mappings between QM observables (such as the electron density) and force field parameters. Examples include automated addition of off-center charges to account for anisotropic electron density, which has not yet been thoroughly explored in protein-ligand binding studies, and higher-order dispersion terms to move beyond the dipole-dipole r -6 interaction. For rapid testing of new force fields, it is desirable to interface with free energy software that can be readily adapted to new force field functional forms whilst achieving efficient performance on modern computing hardware. Options for high-throughput alchemical free energy simulations include Schrödinger's commercial FEP+ package, as well as AMBER and GROMACS. 9 However it is not trivial to modify functional forms in such packages that feature highly optimized routines for efficient evaluation of forces. For this reason, here we implement QUBE in the Sire molecular simulation framework, which includes the SOMD molecular dynamics engine for free energy calculations. SOMD interfaces with the OpenMM toolkit for GPU acceleration, which provides efficient energy evaluation routines whilst allowing flexible definition of force field functional forms via a C++ API. To aid the preparation of QUBE inputs, we make use of the BioSimSpace library, which already facilitates system setup and interoperability between a range of biomolecular simulation packages, such as AMBER, GROMACS, and CHARMM. SOMD has been used within the Sire molecular simulation framework and successfully applied to alchemical free energy studies on a range of drug-like fragments, carbohydrates and host-guest systems. The automated setup and processing of alchemical free energy calculations using Sire, BioSimSpace, SOMD and OpenMM has recently been implemented in Cresset's Flare package, and benchmarked against 220 ligands bound to 14 protein targets, with accuracy comparable to previous reports. Thus, the SOMD framework provides a promising basis for implementation and future benchmarking of alchemical transformations using the QUBE force field. In this paper, we develop and distribute the file parsers that allow users to run QUBE simulations of proteinligand complexes in the Sire and OpenMM molecular simulation frameworks. Following validation of the computational approach, we further demonstrate the use of the QUBE force field in alchemical protein-ligand binding free energy simulations using the protein target HIV-1 reverse transcriptase (RT) as a case study.