Analysis of thermodynamic determinants in helix propensities of nonpolar amino acids through a novel free energy calculation

The relative helix propensities of Gly, Ala, Val, Ile, and Leu in the center of a polyalanine helix were calculated using a novel free energy simulation method (Wang et al. J. Mol. Biol. 1995, 253, 473) that permits the decomposition of the free energy into its various thermodynamic components. The calculated relative free energy changes agree well with the recent set of experimental data of Chakrabartty et al. (Protein Science 1994, 3, 843) on alanine-based peptides. The side chain rotamer distributions in the α-helix produced are also consistent with the reports in the literature based on a statistical survey of crystal structures of proteins. A detailed decomposition of the free energy showed that the solvation effect, or hydrophobicity in particular, has little contribution to the helix propensities of the amino acids relative to Gly. The side chain−helical matrix van der Waals interactions are generally favorable and account for a large part of the free energy change relative to Gly upon helix foldin...