Rearrangements of Water Molecules in Parallel Cascade Selection Molecular Dynamics Enhance Structural Explorations of Proteins

Abstract

Abstract Biological events of proteins are too infrequent to observe with molecular dynamics (MD) simulations, though they are strongly related to the biological functions. To detect such rare events, several enhanced sampling methods have been proposed. Recently, as one of the enhanced sampling methods, we have developed parallel cascade selection molecular dynamics (PaCS-MD). PaCS-MD performs short-time MDs repeatedly from initial structures selected by a given rule as a function of arbitrary reaction coordinates. In the present study, the conventional PaCS-MD is extended as UCHMZ-PaCS-MD, where water coordinates are rearranged before restarting the short-time MDs, which perturb a given system by generating a variety of initial configurations. The restart of short-time MDs from the perturbed systems enables us to further enhance the conformational search. As a demonstration, UCHMZ-PaCS-MD was applied to folding of Chignolin and efficiently identified several metastable states including the intermediate, the misfolding, and the native ones. Furthermore, as a demonstration for globular proteins, large-amplitude domain motions of T4 lysozyme and adenylate kinase were efficiently detected with UCHMZ-PaCS-MD. Additionally, the generated transition pathways were analyzed with Markov state models (MSMs), enabling us to calculate broader free energy landscapes compared with the conventional PaCS-MD.