Frontier Expansion Sampling: A Method to Accelerate Conformational Search by Identifying Novel Seed Structures for Restart.

Abstract

Traditional molecular dynamics (MD) simulations have difficulties in tracking the slow molecular motions, at least partially due to the waste of sampling in already sampled regions. Here, we proposed a new enhanced sampling method, frontier expansion sampling (FEXS), to improve the sampling efficiency of molecular simulations by iteratively selecting seed structures diversely distributed at the "frontier" of an already sampled region to initiate new simulations. Different from other enhanced sampling methods, FEXS identifies the "frontier" seeds by integrating the Gaussian mixture model and the convex hull algorithm, which effectively improves the structural variation among the selected seeds and thus the descendant simulations. Validation in three protein systems, including the folding of chignolin, open-to-closed transition of maltodextrin binding protein, and internal conformational change of bovine pancreatic trypsin inhibitor, confirmed the effectiveness of this novel method in enhancing the sampling of conventional MD simulations to observe the large-scale protein conformational changes. When compared with other enhanced sampling methods like the structural dissimilarity sampling (SDS), FEXS reached at least the same level of sampling efficiency but was capable of providing complementary information in the three tested protein systems.