Estimating the Roles of Protonation and Electronic Polarization in Absolute Binding Affinity Simulations.

ABSTRACT: Accurate prediction of binding free energies is critical to streamlining the drug development and protein design process. With the advent of GPU acceleration, absolute alchemical methods, which simulate the removal of ligand electrostatics and van der Waals interactions with the protein, have become routinely accessible and provide a physically rigorous approach that enables full consideration of flexibility and solvent interaction. However, standard explicit solvent simulations are unable to model protonation or electronic polarization changes upon ligand transfer from water to the protein interior, leading to inaccurate prediction of binding affinities for charged molecules. Here, we perform extensive simulation totaling ∼540 μs to benchmark the impact of modeling conditions on predictiv

SUBMITTER: King E 

PROVIDER: S-EPMC8254375 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature