Receptor-ligand binding and unbinding is a crucial mechanism that governs a range of biological processes, including cellular signaling, enzymatic catalysis, and immunological responses . The interaction between the ligand and receptor enables cells to respond to environmental cues, transmit signals, and carry out essential physiological functions . A comprehensive understanding of the kinetic and thermodynamic properties of receptorligand interactions is essential for designing and optimizing therapeutic agents acting upon specific protein targets . Ligands with a higher residence time (or slow dissociation rates) tend to remain in the binding pocket of the receptor for an extended period, leading to prolonged pharmacological effects. On the other hand, ligands with a lower residence time (or fast dissociation rates) are less likely to produce pharmacological effects . Similarly, the thermodynamic parameters for receptor-ligand interaction, such as affinity, provide insights into the specificity and stability of receptor-ligand binding and unbinding . A complex interplay of kinetic and thermodynamic factors of receptorligand (un)binding determines the duration and strength of interaction between the two entities. Leveraging these factors could aid the development of novel therapeutics, leading to efficient drug discovery and development processes. With recent advancements in computing power and hardware, † Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, California, 92093, United States ‡ Department of Molecular Biology, University of California San Diego, La Jolla, California, 92093, United States; E-mail: ramaro@ucsd.edu molecular dynamics (MD) simulations have emerged as a powerful tool for studying the kinetics and thermodynamics of molecular interactions . Despite such progress, MD simulations have limitations when studying complex biological processes, such as protein folding and unfolding , large protein conformational rearrangements , and receptor-ligand binding and unbinding due to the relatively long timescales needed to observe such events . These phenomena may occur on a timescale of milliseconds or longer, and it becomes increasingly difficult for MD simulations to rigorously characterize such events. Enhanced MD simulations accelerate the conformational search of the system, thereby allowing rare events to be observed within a reasonable computational time . Enhanced MD simulations can be roughly categorized into collective variable (CV) free and CV-based approaches. CV-based approaches include metadynamics , Markov state models (MSMs) , variationally enhanced sampling , weighted ensemble, and umbrella sampling , CV-free approaches include accelerated molecular dynamics (aMD) , Gaussian accelerated molecular dynamics (GaMD) , replica exchange molecular dynamics (REMD) , and selective integrated tempering .