Use of Locally Enhanced Sampling in Free Energy Calculations: Testing and Application to the α → β Anomerization of Glucose

Abstract

We present a new approach to calculating conformational equilibria in complex molecules, multiple-copy locally enhanced sampling (LES), and apply this approach to the well-known α → β anomeric equilibrium in glucose. Although a variant of this method has been previously applied to protein stability mutations, it is particularly suited to analyze conformational equilibria in molecules such as glucose, with its many OH groups. This methodology allows us to more rapidly calculate complex equilibria both in vacuo and in solution. We have employed a “generic” force field using 1,1-dimethoxymethane and 1,1-dihydroxymethane as models to derive the torsional parameters associated with O−C−O−C and O−C−O−H fragments. Within this model, we can definitively establish the magnitude of intramolecular and solvation contributions to the α → β equilibrium. Specifically, we find that in vacuo glucose prefers to be in the α configuration by ∼0.5−1.0 kcal/mol (predominantly because of the gauche tendency of the O−C−O−C linka...