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 energ y simulation method (Wang et al. J. Mol. Biol. 1995, 253, 473) that pe rmits the decomposition of the free energy into its various thermodyna mic components. The calculated relative free energy changes agree well with the recent set of experimental data of Chakrabartty et al. (Prot ein Science 1994, 3, 843) on alanine-based peptides. The side chain ro tamer distributions in the alpha-helix produced are also consistent wi th the reports in the literature based on a statistical survey of crys tal structures of proteins. A detailed decomposition of the free energ y showed that the solvation effect, or hydrophobicity in particular, h as little contribution to the helix propensities of the amino acids re lative to Gly. The side chain-helical matrix van der Waals interaction s are generally favorable and account for a large part of the free ene rgy change relative to Gly upon helix folding. The configurational ent ropy plays a significant, but not dominant, role in the relative free energy changes. The absolute change of configurational entropy of a ce ntral amino acid in folding, which is usually difficult to assess, was also obtained. The entropic cost of restricting the backbone of an am ino acid in a helical matrix is about 1.5 kcal/mol at 25 degrees C, si gnificantly larger than the cost associated with the reduction in side chain entropy in the helix.