Applying Absolute Free Energy Perturbation Molecular Dynamics to Diffusively Binding Ligands.

ABSTRACT: We have developed and tested an absolute free energy perturbation (FEP) protocol, which combines all-atom molecular dynamics, replica exchange with solute tempering (REST) enhanced sampling, and a spherical harmonic restraint applied to a ligand. Our objective was to compute the binding free energy together with the underlying binding mechanism for a ligand, which binds diffusively to a protein. Such ligands represent nearly impossible targets for traditional FEP simulations. To test our FEP/REST protocol, we selected a conserved motif peptide KKPK termed minNLS from the nuclear localization signal sequence of the Venezuelan equine encephalitis virus capsid protein. This peptide fragment binds diffusively to importin-α transport protein without forming well-defined poses. Our FEP/REST simu

SUBMITTER: Laracuente XE 

PROVIDER: S-EPMC12020361 | biostudies-literature | 2025 Apr

REPOSITORIES: biostudies-literature