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 folding. The configurational entropy plays a significant, but not dominant, role in the relative free energy changes. The absolute change of configurational entropy of a central amino acid in folding, which is usually difficult to assess, was also obtained. The entropic cost of restricting the backbone of an amino acid in a helical matrix is about 1.5 kcal/mol at 25 °C, significantly larger than the cost associated with the reduction in side chain entropy in the helix.