Nontargeted Parallel Cascade Selection Molecular Dynamics Based on a Nonredundant Selection Rule for Initial Structures Enhances Conformational Sampling of Proteins.

Nontargeted parallel cascade selection molecular dynamics (nt-PaCS-MD) is a method for enhanced conformational sampling of proteins. To search a broad conformational subspace, nt-PaCS-MD repeats cycles of conformational resampling from relevant initial structures. Generally, the conformational sampling efficiency of nt-PaCS-MD depends on a selection rule for the initial structures. In the original nt-PaCS-MD, the initial structures were selected by referring to structural distributions of protein configurations generated by conformational resampling (multiple short-time MD simulations). However, their structural redundancy among the initial structures was neglected for the cycles of conformational resampling, indicating that similar protein configurations might be frequently specified and resampled in every cycle in the original nt-PaCS-MD. To reduce the possibility of resampling from redundant initial structures, we propose an alternative selection rule that accounts for structural similarity among the initial structures. Specifically, a pairwise root-mean-square deviation (RMSD) is defined for all of the initial structures selected for all of the past cycles. Then a set of protein configurations with a larger pairwise RMSD is sequentially specified and resampled in the next cycle, which is regarded to as a history-dependent selection of initial structures by considering a profile of the past specified initial structures. The present scheme, termed extended nt-PaCS-MD, prevents us from resampling a set of redundant protein configurations. To check the conformational sampling efficiency of the extended nt-PaCS-MD, we used a middle-sized protein, T4 lysozyme, in explicit water. Through the assessment, this extended nt-PaCS-MD identified the open-closed transitions of T4 lysozyme more efficiently than the original nt-PaCS-MD.