Multicanonical ab inito QM/MM molecular dynamics simulation of a peptide in an aqueous environment.

We developed a multicanonical ab initio QM/MM molecular dynamics simulation method to enhance conformational sampling of biomolecules in an aqueous environment. We applied this method to an alanine dipeptide immersed in a sphere of explicit water molecules. The peptide and the water molecules were treated by the QM method at the HF/3-21G level and by the MM method, respectively. The van der Waals interactions between the peptide and the water molecules were calculated at the MM level, while the electrostatic interaction terms between them were incorporated into the QM Hamiltonian to account for the effect of the solvent on the electronic structure of the peptide. The simulation was performed for 1 ns, and a free-energy map was calculated with respect to the peptide conformation. All the conformations (C(5), P(II), C(7eq), and alpha(R)) that have been experimentally suggested to exist in solution formed basins on the free-energy surface. Analysis of the water distribution revealed that the alpha(R) conformation was stabilized by the interaction between the large electric dipole moments of this peptide conformation and the water electric dipole moments, whereas the P(II) conformation was stabilized by the formation of characteristic hydrogen bonds with the water molecules. 2009 Wiley Periodicals, Inc.