CONFORMATIONAL EQUILIBRIUM IN THE ALANINE DIPEPTIDE IN THE GAS-PHASE AND AQUEOUS-SOLUTION - A COMPARISON OF THEORETICAL RESULTS

The acetyl and methyl amide blocked alanine amino acid, commonly referred to as the alanine dipeptide, has often been used as a model in theoretical studies of backbone conformational equilibria in proteins. In order to evaluate the solvent effects on the conformational equilibrium of the dipeptide, we have used molecular dynamics simulations with holonomic backbone dihedral angle constraints and thermodynamic perturbation theory to calculate free energy profiles along paths connecting four important conformations of the dipeptide in the gas phase and in water. We found that the extended beta-conformation is the most stable both in the gas phase and in water. The C7ax conformation (seven-membered ring closed by a hydrogen bond with axial methyl group) is less stable than the beta-conformation by 2.4 kcal/mol in the gas phase and 3.6 kcal/mol in water. The right- and left-handed alpha-helical conformations, alpha(R) and alpha(L), are less stable than the beta-conformation by 9.1 and 11.6 kcal/mol, respectively, in the gas phase. However, in aqueous solution the alpha(R) and alpha(L) conformations are less stable than the beta-conformation by only 0.2 and 4.1 kcal/mol, respectively. Thus, we found, as others have previously, that there is a marked solvent effect on the backbone conformational equilibrium. We have determined the energetic and entropic contributions to the free energies to explain the relative stabilities of the dipeptide conformations in terms of differences in peptide-peptide and peptide-solvent interactions. Finally, we have compared our results to the results of several previous theoretical studies of the alanine dipeptide.