Parametrization of GROMOS force field for oligosaccharides and assessment of efficiency of molecular dynamics simulations

Molecular dynamics (MD) simulations of α‐D‐maltose (maltose) in vacuo and with explicit inclusion of water were performed using the GROMOS force field that was modified to include a potential energy term for the exo‐anomeric effect. Different simulation temperatures, the influence of the size of the water box, and carbohydrate‐specific force field parameter values were evaluated with respect to sampling efficiency and average conformations. First, maltose was surrounded by 500 water molecules and simulated for 750 ps. Furthermore, three 500‐ps MD simulations in vacuo were run to identify the effect of solvation on the location of the preferred conformation and on the flexibility of the molecule. Inclusion of water leads to a change of the preferred conformation from ϕ/ψ1 ≅ −20°/−17° in vacuo to −40°/−31° in aqueous solution. The explicit incorporation of water molecules into the simulation gave rise to only short‐lived hydrogen bond interactions. In particular, a hydrogen bond found in vacuo from OH3 of the reducing glucose to O2′ of the nonreducing glucose was rarely present when water was included in the simulation. In vacuo the conformational freedom of the glycosidic linkage and the hydroxymethyl and hydroxyl groups were strongly reduced due to intramolecular hydrogen bonds. Two 200‐ps MD runs with inclusion of 137 water molecules at temperatures of 350 and 400 K showed the expected increase of the transitions between the rotamers of the hydroxymethyl groups. An equilibrium for the conformation of the glycosidic linkage was only reached when raising the temperature parameter of the MD simulation further to 600 K. However, at this temperature inversions of the pyranose ring were already observed within a 1‐ns MD simulation. Parametrization of GROMOS to include the exo‐anomeric effect proved to be necessary because the previously published force field has no provisions to account for the exo‐anomeric effect, as revealed by two MD simulations in water and in vacuo that indicated a significant population at positive ϕ angles. Using dimethoxymethane as a model for the O‐glycosidic linkage, the empirical potential function for the rotation about the C1(SINGLE BOND)O1 bond was adjusted to represent the potential calculated by STO 6–31G* ab initio calculations. MD simulations using the adjusted force field revealed a reduced population with positive ϕ values. A separate parametrization of the potential for the reducing hydroxyl group of saccharides resulted in a better description of the conformation, as well as increased stability of the integration algorithm. Finally, the existing GROMOS force field was supplemented by an additional gauche potential. Its effect on the conformation of the hydroxymethyl groups was evaluated by a 500‐ps MD simulation in water. © 1996 by John Wiley & Sons, Inc.