Efficient Conformational Sampling of Collective Motions of Proteins with Principal Component Analysis-Based Parallel Cascade Selection Molecular Dynamics.

Molecular dynamics (MD) simulation has become a powerful tool because it provides a time series of protein dynamics at high temporal-spatial resolution. However, the accessible timescales of MD simulation are shorter than those of the biologically rare events. Generally, long-time MD simulations over microseconds are required to detect the rare events. Therefore, it is desirable to develop rare-event-sampling methods. For a rare-event-sampling method, we have developed parallel cascade selection MD (PaCS-MD). PaCS-MD generates transition pathways from a given source structure to a target structure by repeating short-time MD simulations. The key point in PaCS-MD is how to select reasonable candidates (protein configurations) with high potentials to make transitions toward the target structure. In the present study, based on principal component analysis (PCA), we propose PCA-based PaCS-MD to detect rare events of collective motions of a given protein. Here, the PCA-based PaCS-MD is composed of the following two steps. At first, as a preliminary run, PCA is performed using an MD trajectory from the target structure to define a principal coordinate (PC) subspace for describing the collective motions of interest. PCA provides principal modes as eigenvectors to project a protein configuration onto the PC subspace. Then, as a production run, all the snapshots of short-time MD simulations are ranked by inner products (IPs), where an IP is defined between a snapshot and the target structure. Then, snapshots with higher values of the IP are selected as reasonable candidates, and short-time MD simulations are independently restarted from them. By referring to the values of the IP, the PCA-based PaCS-MD repeats the short-time MD simulations from the reasonable candidates that are highly correlated with the target structure. As a demonstration, we applied the PCA-based PaCS-MD to adenylate kinase and detected its large-amplitude (open-closed) transition with a nanosecond-order computational cost.