Nontargeted Parallel Cascade Selection Molecular Dynamics for Enhancing the Conformational Sampling of Proteins

Nontargeted parallel cascade selection molecular dynamics (nt-PaCS-MD) is proposed as an efficient conformational sampling method to enhance the conformational transitions of proteins, which is an extension of the original targeted PaCS-MD (t-PaCS-MD). The original PaCS-MD comprises cycles of (i) selection of initial structures for multiple independent MD simulations toward a predetermined target and (ii) conformational sampling by the independent MDs. In nt-PaCS-MD, structures that significantly deviate from an average are regarded as candidates that have high potential to address other metastable states and are chosen as the initial structures in the selection. To select significantly deviated structures, we examine the root-mean-square deviation (RMSD) of snapshots generated from the average structure based on Gram-Schmidt orthogonalization. nt-PaCS-MD was applied to the folding of the mini-protein chignolin in implicit solvent and to the open-closed conformational transitions of T4 lysozyme (T4L) and glutamine binding protein (QBP) in explicit solvent. We show that nt-PaCS-MD can reach chignolin's native state and can also cause the open-closed transition of T4L and QBP on a nanosecond time scale, which are very efficient in terms of conformational sampling and comparable to that with t-PaCS-MD.