Accurate predictions of protein-ligand binding poses and affinities have been a central challenge in computational chemistry. Molecular dynamics simulation provides a rigorous way to predict the binding poses. However, the ligand is often trapped at wrong poses, resulting in the slow convergence of the simulation. To overcome the difficulty, we here propose a pose-refinement method based on the generalized replica exchange with solute tempering (gREST) [1] which is implemented in GENESIS [2]. The protein-ligand interaction is weakened at high temperatures, accelerating the sampling of multiple poses. To avoid ligand dissociation at high temperatures, a half flat-bottomed restraint potential centered on the binding site is applied. Using the free energy perturbation (FEP) method, we calculated binding affinities of obtained poses, showing excellent agreement between the calculated and experimental results. The present gREST+FEP protocol requires small number of replicas (around ten). The method is general and would help to predict the binding affinities of a ligand toward a target protein without high-resolution bound state structural information.<br/>

Refinement of protein-ligand binding poses using the generalized ensemble method

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.