Helix propensity of Ala and Val: a free energy perturbation study

Difference in helix propensity between Ala and Val was examined by a molecular dynamics/free energy perturbation method. Simulations were based on a simple two state model of helix-coil transition. Val10 in an Ala based 17mer peptide (Y1K2A3A4A5A6K7A8A9V10A11K12A13A14A15A16K17) used as the alpha-helical model, or in an extended trimer (A9V10A11) used as the random coil model, was perturbed to Ala by a slow growth method. The computed delta delta G (-1.27 +/- 0.92 kcal/mol) reproduced semiquantitatively the experimental delta delta G (-0.7 kcal/mol; Padmanabhan et al., Nature 344 (1990) 268). Inclusion of intraperturbed contributions was essential. Free energy component analysis showed that intra-perturbed interaction within Va10 contributed positive value to delta delta G and that interaction between Lys7 and Val10 contributed negative value. The latter dominated the former, which resulted in the larger helix propensity of Ala.