Enhancing Sampling of the Conformational Space Near the Protein Native State

Abstract

A protein molecule assumes specific conformations under native conditions to fit and interact with other molecules. Due to the role that three-dimensional structure plays in protein function, significant efforts are devoted to elucidating native conformations. Many search algorithms are proposed to navigate the high-dimensional protein conformational space and its underlying energy surface in search of low-energy conformations that comprise the native state. In this work, we identify two strategies to enhance the sampling of native conformations. We show that employing an enhanced fragment library with greater structural diversity to assemble low-energy conformations allows sampling more native conformations. To efficiently handle the ensuing vast conformational space, only a representative subset of the sampled conformations are maintained and employed to further guide the search for native conformations. Our results show that these two strategies greatly enhance the sampling of the conformational space near the native state.