Studying the Collective Functional Response of a Receptor in Alchemical Ligand Binding Free Energy Simulations with Accelerated Solvation Layer Dynamics

Jiang, Wei

doi:10.1021/acs.jctc.4c00191

Studying the Collective Functional Response of a Receptor in Alchemical Ligand Binding Free Energy Simulations with Accelerated Solvation Layer Dynamics

Journal Article · Wed Apr 03 00:00:00 EDT 2024 · Journal of Chemical Theory and Computation

DOI:https://doi.org/10.1021/acs.jctc.4c00191· OSTI ID:2474889

^[1]

Argonne National Laboratory (ANL), Argonne, IL (United States)

Ligand binding free energy simulations (LB-FES) that involve sampling of protein functional conformations have been longstanding challenges in research on molecular recognition. Particularly, modeling of the conformational transition pathway and design of the heuristic biasing mechanism are severe bottlenecks for the existing enhanced configurational sampling (ECS) methods. Inspired by the key role of hydration in regulating conformational dynamics of macromolecules, this report proposes a novel ECS approach that facilitates binding-associated structural dynamics by accelerated hydration transitions in combination with the lambda-exchange of free energy perturbation (FEP). Further, two challenging protein-ligand binding processes involving large configurational transitions of the receptor are studied, with hydration transitions at binding sites accelerated by Hamiltonian-simulated annealing of the hydration layer. Without the need for pathway analysis or ad hoc barrier flattening potential, LB-FES were performed with FEP/lambda-exchange molecular dynamics simulation at a minor overhead for annealing of the hydration layer. The LB-FES studies showed that the accelerated rehydration significantly enhances the collective conformational transitions of the receptor, and convergence of binding affinity calculations is obtained at a sweet-spot simulation time scale. Alchemical LB-FES with the proposed ECS strategy is free from the effort of trial and error for the setup and realizes efficient on-the-fly sampling for the collective functional response of the receptor and bound water and therefore presents a practical approach to high-throughput screening in drug discovery.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: National Institutes of Health (NIH); USDOE Office of Science

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 2474889

Journal Information:: Journal of Chemical Theory and Computation, Journal Name: Journal of Chemical Theory and Computation Journal Issue: 8 Vol. 20; ISSN 1549-9618

Publisher:: American Chemical SocietyCopyright Statement

Country of Publication:: United States

Language:: English

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Studying the Collective Functional Response of a Receptor in Alchemical Ligand Binding Free Energy Simulations with Accelerated Solvation Layer Dynamics

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