Conformational Free Energy Surfaces of Ala10and Aib10Peptide Helices in Solution

A newly developed molecular simulation algorithm, the multidimensional conformational free energy thermodynamic integration (CFTI) method, has been applied to describe the conformational free energy surfaces of regular peptide helices in solution. The systems studied are (Ala) 10 and (Aib) 10 peptides, where Aib is α-methylalanine, in water and DMSO solution. The CFTI approach was used to calculate two-dimensional maps of the conformational free energy and its gradient as a function of the peptide backbone dihedrals (φ,ψ). In the region of right-handed helical structures of (Ala) 10 and (Aib) 10, the α-helix and π-helix were found to be locally stable states, corresponding to free energy minima. The location of the minima was refined by free energy optimization. Unexpectedly, solvation by both water and DMSO tended to strongly stabilize the π-helix relative to the standard α-helical structure. The π and α-helices had essentially identical stability for (Ala) 10 in water and DMSO. The (Ala) 10 π-helical free energy minima found in our simulations at (φ,ψ) = (−75°,−56°) in water and at (−78°,−53°) in DMSO were markedly different from the generally accepted model values of (−57°,−70°). Our structure had strong favorable interactions with solvent, low internal strain, and a volume identical to that of an α-helix, suggesting that π-helices should be considered as possible peptide conformers worthy of further computational and experimental studies. The 3 10 -helix was significantly less stable than the other regular helix types in solution, and no minima corresponding to the 3 10 -helix were found in any of the solvated systems, in contrast to previous vacuum simulations for Aib peptides. Energetic and structural features of the different helices were analyzed to provide a microscopic explanation of the stability differences. The large solvation effects and general conformational trends could be rationalized in terms of the interplay between the quality and quantity of intramolecular hydrogen bonds on the one hand and solute−solvent interactions on the other. A relatively inexpensive scheme using vacuum simulations with an approximate solvation correction consisting of a surface term and a Poisson−Boltzmann electrostatic term was able to reproduce the explicit solvent simulation results.