Independent Nontargeted Parallel Cascade Selection Molecular Dynamics (Ino-PaCS-MD) to Enhance the Conformational Sampling of Proteins.

Biological functions are related to long-time protein dynamics (rare events) that are induced over microseconds. Such protein dynamics can be investigated using molecular dynamics (MD) simulations. However, the detection of rare events remains challenging using conventional MD (cMD) since the accessible timescales of cMD are shorter than those of the biological functions. Recently, the parallel cascade selection MD (PaCS-MD) has been proposed to detect such rare events, wherein transition paths are generated between a given reactant and product. As an extension, the nontargeted PaCS-MD (nt-PaCS-MD) has been proposed to predict the transition paths without requiring reference to any product. Thus, as a further extension, we herein propose independent nt-PaCS-MD, namely, Ino-PaCS-MD, wherein multiple walkers are launched from a set of different starting configurations. Each walker repeats a cycle of restarting short-time MD simulations from configurations with high potentials for making transitions to neighboring metastable states. To further enhance the sampling ability, Ino-PaCS-MD temporarily stops the conformational search and periodically resets the starting configurations so that they are uniformly distributed in a conformational subspace, thereby preventing a given protein from being trapped in one of the metastable states. As a demonstration, Ino-PaCS-MD successfully detects rare events of a maltose-binding protein as open-close transitions with a nanosecond-order simulation time, although a microsecond-order cMD simulation failed to detect these rare events, showing the high sampling efficiency of Ino-PaCS-MD.