Conformational free energy surfaces of Ala(10) and Aib(10) peptide helicesin solution

J. Mahadevan et al., Conformational free energy surfaces of Ala(10) and Aib(10) peptide helicesin solution, J PHYS CH B, 105(9), 2001, pp. 1863-1876
Citations number
Categorie Soggetti
Physical Chemistry/Chemical Physics
Journal title
ISSN journal
1520-6106 → ACNP
Year of publication
1863 - 1876
SICI code
A newly developed molecular simulation algorithm, the multidimensional conf ormational free energy thermodynamic integration (CFTI) method, has been ap plied to describe the conformational free energy surfaces of regular peptid e helices in solution. The systems studied are (Ala)(10) and (Aib)(10) pept ides, where Aib is alpha -methylalanine, in water and DMSO solution. The CE TI approach was used to calculate two-dimensional maps of the conformationa l free energy and its gradient as a function of the peptide backbone dihedr als (phi,psi). In the region of right-handed helical structures of (Ala)lo and (Aib)(10), the alpha -helix and, pi -helix were found to be locally sta ble states, corresponding to free energy minima. The location of the minima was refined by free energy optimization. Unexpectedly, solvation by both w ater and DMSO tended to strongly stabilize the pi -helix relative to the st andard alpha -helical structure. The pi and alpha -helices had essentially identical stability for (Ala)lo in water and DMSO. The (Ala)(10) pi -helica l free energy minima found in our simulations at (phi,psi) = (-75 degrees,- 56 degrees) in water and at (-78 degrees,-53 degrees) in DMSO were markedly different from the generally accepted model values of (-57 degrees,-70 deg rees). Our structure had strong favorable interactions with solvent, low in ternal strain. and a volume identical to that of an alpha -helix, suggestin g thar, alpha -helices should be considered as possible peptide conformers worthy of further computational and experimental studies. The 3(10)-helix w as 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 s olvated systems, in contrast to previous vacuum simulations for Aib peptide s. Energetic and structural features of the different helices were analyzed to provide a microscopic explanation of the stability differences. The lar ge solvation effects and general conformational trends could be rationalize d in terms of the interplay between the quality and quantity of intramolecu lar hydrogen bonds on the one hand and solute-solvent interactions on the o ther. A relatively inexpensive scheme using vacuum simulations with an appr oximate solvation correction consisting of a surface term and a Poisson-Bol tzmann electrostatic term was able to reproduce the explicit solvent simula tion results.