Exploring the Transferability of Replica Exchange Structure Reservoirs to Accelerate Generation of Ensembles for Alternate Hamiltonians or Protein Mutations.

Abstract

Generating precise ensembles is commonly a prerequisite to understand the energetics of biological processes using Molecular Dynamics (MD) simulations. Previously, we have shown how unweighted reservoirs built from high temperature MD simulations can accelerate convergence of Boltzmann-weighted ensembles by at least 10× with the Reservoir Replica Exchange MD (RREMD) method. Therefore, in this work, we explore whether an unweighted structure reservoir generated with one Hamiltonian (solute force field plus solvent model) can be reused to quickly generate accurately weighted ensembles for Hamiltonians other than the one that was used to generate the reservoir. We also extended this methodology to rapidly estimate the effects of mutations on peptide stability by using a reservoir of diverse structures obtained from wild-type simulations. These results suggest that structures generated via fast methods such as coarse-grained models or structures predicted by Rosetta or deep learning approaches could be integrated into a reservoir to accelerate generation of ensembles using more accurate representations.