Efficient sampling of puckering states of monosaccharides through replica exchange with solute tempering and bond softening.

Abstract

A molecular-level understanding of the structure, dynamics, and reactivity of carbohydrates is fundamental to the understanding of a range of key biological processes. The six-membered pyranose ring, a central component of biological monosaccharides and carbohydrates, has many different puckering conformations, and the conformational free energy landscape of these biologically important monosaccharides remains elusive. The puckering conformations of monosaccharides are separated by high energy barriers, which pose a great challenge for the complete sampling of these important conformations and accurate modeling of these systems. While metadynamics or umbrella sampling methods have been used to study the conformational space of monosaccharides, these methods might be difficult to generalize to other complex ring systems with more degrees of freedom. In this paper, we introduce a new enhanced sampling method for the rapid sampling over high energy barriers that combines our previously developed enhanced sampling method REST (replica exchange with solute tempering) with a bond softening (BOS) scheme that makes a chemical bond in the ring weaker as one ascends the replica ladder. We call this new method replica exchange with solute tempering and bond softening (REST/BOS). We demonstrate the superior sampling efficiency of REST/BOS over other commonly used enhanced sampling methods, including temperature replica exchange method and REST. The conformational free energy landscape of four biologically important monosaccharides, namely, α-glucose, β-glucose, β-mannose, and β-xylose, is studied using REST/BOS, and results are compared with previous experimental and theoretical studies.