PARAMETRIZATION OF GROMOS FORCE-FIELD FOR OLIGOSACCHARIDES AND ASSESSMENT OF EFFICIENCY OF MOLECULAR-DYNAMICS SIMULATIONS

Molecular dynamics (MD) simulations of alpha-D-maltose (maltose) in va cuo and with explicit inclusion of water were performed using the GROM OS force field that was modified to include a potential energy term fo r the exo-anomeric effect. Different simulation temperatures, the infl uence of the size of the water box, and carbohydrate-specific force fi eld parameter values were evaluated with respect to sampling efficienc y and average conformations. First, maltose was surrounded by 500 wate r molecules and simulated for 750 ps. Furthermore, three 500-ps MD sim ulations in vacuo were run to identify the effect of solvation on the location of the preferred conformation and on the flexibility of the m olecule. Inclusion of water leads to a change of the preferred conform ation from phi/psi(1) approximate to -20 degrees/-17 degrees in vacuo to -40 degrees/-31 degrees in aqueous solution. The explicit incorpora tion of water molecules into the simulation gave rise to only short-li ved hydrogen bond interactions. In particular, a hydrogen bond found i n vacuo from OH3 of the reducing glucose to O2' of the nonreducing glu cose was rarely present when water was included in the simulation. In vacuo the conformational freedom of the glycosidic linkage and the hyd roxymethyl and hydroxyl groups were strongly reduced due to intramolec ular hydrogen bonds. Two 200-ps MD runs with inclusion of 137 water mo lecules at temperatures of 350 and 400 K showed the expected increase of the transitions between the rotamers of the hydroxymethyl groups. A n equilibrium for the conformation of the glycosidic linkage was only reached when raising the temperature parameter of the MD simulation fu rther to 600 K. However, at this temperature inversions of the pyranos e ring were already observed within a l-ns MD simulation. Parametrizat ion of GROMOS to include the exo-anomeric effect proved to be necessar y because the previously published force field has no provisions to ac count for the exo-anomeric effect, as revealed by two MD simulations i n water and in vacuo that indicated a significant population at positi ve phi angles. Using dimethoxymethane as a model for the O-glycosidic linkage, the empirical potential function for the rotation about the C 1-O1 bond was adjusted to represent the potential calculated by STO 6- 31G ab initio calculations. MD simulations using the adjusted force f ield revealed a reduced population with positive phi values. A separat e parametrization of the potential for the reducing hydroxyl group of saccharides resulted in a better description of the conformation, as w ell as increased stability of the integration algorithm. Finally, the existing GROMOS force field was supplemented by an additional gauche p otential. Its effect on the conformation of the hydroxymethyl groups w as evaluated by a 500-ps MD simulation in water. (C) 1996 by John Wile y & Sons, Inc.