Improved carbohydrate force field for GROMOS: ring and hydroxymethyl groupconformations and exo-anomeric effect

In this work, improvements of the carbohydrate force field for GROMOS have been carried out by combined molecular mechanics (MM) and molecular dynamic s (MD) calculations. With the original force field, a far too small relativ e energy (4.5 kJ mol(-1)) between the 'normal' chair conformation (C-4(1)) and the 'inverted chair' conformation (C-1(4)) of the methyl beta-D-glucopy ranoside has been observed in vacuum, compared with ab initio and MM3 calcu lations that predict 16.0-30.0 kJ mol(-1). The ring inversion has been solv ed by a large increase of the bond-angle force constants involving the oxyg en 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 beta-D- glucopyranoside and methyl beta-D-galactopyranoside, it has been found that the rotamer distribution of the hydroxymethyl group does not reproduce acc urately NMR data. The hydroxymethyl group conformer distribution has been i mproved by increasing the torsional barrier around the considered bond (OA- CS2-CS1-OS) leading to a closer agreement with experimental rotamer distrib utions. In addition, an improved dihedral potential has been used to accoun t for the exo-anomeric effect. MM calculations in vacuum on the methyl beta -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. (C) 1999 Elsevier Science Ltd. All rights reserved.