Combination of molecular dynamics method and 3D-RISM theory for conformational sampling of large flexible molecules in solution.

We have developed an algorithm for sampling the conformational space of large flexible molecules in solution, which combines the molecular dynamics (MD) method and the three-dimensional reference interaction site model (3D-RISM) theory. The solvent-induced force acting on solute atoms was evaluated as the gradient of the solvation free energy with respect to the solute-atom coordinates. To enhance the computation speed, we have applied a multiple timestep algorithm based on the RESPA (Reversible System Propagator Algorithm) to the combined MD/3D-RISM method. By virtue of the algorithm, one can choose a longer timestep for renewing the solvent-induced force compared with that of the conformational update. To illustrate the present MD/3D-RISM simulation, we applied the method to a model of acetylacetone in aqueous solution. The multiple timestep algorithm succeeded in enhancing the computation speed by 3.4 times for this model case. Acetylacetone possesses an intramolecular hydrogen-bonding capability between the hydroxyl group and the carbonyl oxygen atom, and the molecule is significantly stabilized due to this hydrogen bond, especially in gas phase. The intramolecular hydrogen bond was kept intact during almost entire course of the MD simulation in gas phase, while in the aqueous solutions the bond is disrupted in a significant number of conformations. This result qualitatively agrees with the behavior on a free energy barrier lying upon the process for rotating a torsional degree of freedom of the hydroxyl group, where it is significantly reduced in aqueous solution by a cancellation between the electrostatic interaction and the solvation free energy. (c) 2007 Wiley Periodicals, Inc.