Improved carbohydrate force field for gromos: ring and hydroxymethyl group conformations and exo-anomeric effect

Abstract

In this work, improvements of the carbohydrate force field for gromos have been carried out by combined molecular mechanics (MM) and molecular dynamics (MD) calculations. With the original force field, a far too small relative energy (4.5 kJ mol −1) between the ‘normal’ chair conformation ( 4 C 1) and the ‘inverted chair’ conformation ( 1 C 4) of the methyl β- d-glucopyranoside has been observed in vacuum, compared with ab initio and MM3 calculations that predict 16.0–30.0 kJ mol −1. The ring inversion has been solved by a large increase of the bond-angle force constants involving the oxygen atom of hydroxyl groups. The consequence of such a modification for the relative energy between the two chair conformations is an increase to 13.2 kJ mol −1. Furthermore using a potential-of-mean-force calculation through umbrella sampling, with explicit solvent molecules, on both methyl β- d-glucopyranoside and methyl β- d-galactopyranoside, it has been found that the rotamer distribution of the hydroxymethyl group does not reproduce accurately NMR data. The hydroxymethyl group conformer distribution has been improved by increasing the torsional barrier around the considered bond (OACS2CS1OS) leading to a closer agreement with experimental rotamer distributions. In addition, an improved dihedral potential has been used to account for the exo-anomeric effect. MM calculations in vacuum on the methyl β- d-fructofuranoside have shown that our force field modifications have only a slight influence on the conformation of the five-membered ring. This was confirmed by MD simulation in aqueous solution.