Exploring Configuration Space and Path Space of Biomolecules Using Enhanced Sampling Techniques—Searching for Mechanism and Kinetics of Biomolecular Functions

Abstract

To understand functions of biomolecules such as proteins, not only structures but their conformational change and kinetics need to be characterized, but its atomistic details are hard to obtain both experimentally and computationally. Here, we review our recent computational studies using novel enhanced sampling techniques for conformational sampling of biomolecules and calculations of their kinetics. For efficiently characterizing the free energy landscape of a biomolecule, we introduce the multiscale enhanced sampling method, which uses a combined system of atomistic and coarse-grained models. Based on the idea of Hamiltonian replica exchange, we can recover the statistical properties of the atomistic model without any biases. We next introduce the string method as a path search method to calculate the minimum free energy pathways along a multidimensional curve in high dimensional space. Finally we introduce novel methods to calculate kinetics of biomolecules based on the ideas of path sampling: one is the Onsager–Machlup action method, and the other is the weighted ensemble method. Some applications of the above methods to biomolecular systems are also discussed and illustrated.

Keywords

• molecular dynamics simulation
• rare event
• string method
• multiscale enhanced sampling
• weighted ensemble
• multidrug transporter
• Onsager–Machlup action