Molecular dynamics (MD) simulations that capture the spontaneous binding of drugs and other ligands to their target proteins can reveal a great deal of useful information, but most drug-like ligands bind on time scales longer than those accessible to individual MD simulations. Adaptive sampling methods-in which one performs multiple rounds of simulation, with the initial conditions of each round based on the results of previous rounds-offer a promising potential solution to this problem. No comprehensive analysis of the performance gains from adaptive sampling is available for ligand binding, however, particularly for protein-ligand systems typical of those encountered in drug discovery. Moreover, most previous work presupposes knowledge of the ligand's bound pose. Here we outline existing methods for adaptive sampling of the ligand-binding process and introduce several improvements, with a focus on methods that do not require prior knowledge of the binding site or bound pose. We then evaluate these methods by comparing them to traditional, long MD simulations for realistic protein-ligand systems. We find that adaptive sampling simulations typically fail to reach the bound pose more efficiently than traditional MD. However, adaptive sampling identifies multiple potential binding sites more efficiently than traditional MD and also provides better characterization of binding pathways. We explain these results by showing that protein-ligand binding is an example of an exploration-exploitation dilemma. Existing adaptive sampling methods for ligand binding in the absence of a known bound pose vastly favor the broad exploration of protein-ligand space, sometimes failing to sufficiently exploit intermediate states as they are discovered. We suggest potential avenues for future research to address this shortcoming.

This work describes an example of using Unbiased molecular dynamics simulation in kinetic calculations.

The following methods are also used: