FREE-ENERGY DETERMINANTS OF SECONDARY STRUCTURE FORMATION .1. ALPHA-HELICES

The Zimm-Bragg parameters s and sigma are calculated for the helix-coi l transition of poly-L-alanine. The theoretical approach involves eval uating gas phase conformational energies for both coil and helical sta tes using the CHARMM potential function and accounting for solvation e ffects with various continuum solvation models. Conformational free en ergies are then incorporated into a formalism developed by Go et al. f or the calculation of s and sigma. Calculated values for both sand sig ma as well as the enthalpy change associated with helix formation are in good agreement with experimental data when the Finite Difference Po isson-Boltzmann (FDPB) method is used to treat solvent effects. The dr iving force for the helix-coil transition is analyzed in terms of indi vidual free energy components. Hydrogen bond formation is found to con tribute little to helix stability because the internal hydrogen bondin g energy is largely canceled by the large free energy cost associated with removing polar groups from water. The entropic cost associated wi th fixing backbone dihedral angles in the helical conformation is foun d to be similar to 7 e.u./residue (about 2 kcal/mol at room temperatur e). The major driving force favoring helix formation can be associated with interactions including enhanced van der Waals interactions in th e close-packed helix conformation and the hydrophobic effect. These co ntribute about 2 kcal/mol favoring the helical state. The differences in helical propensities between alanine and glycine are attributed pri marily to hydrophobic and packing interactions involving the C-beta Wi th a Smaller contribution arising from increased conformational freedo m for glycine in the coil state. The description of helix formation pr esented here is consistent with previous conclusions regarding tertiar y structure formation which suggest that hydrophobic and close-packed interactions provide stability while hydrogen bond formation constitut es a structural constraint imposed by the high free energy cost associ ated with burying unsatisfied hydrogen bonding groups. alpha-Helix for mation may thus be viewed as a form of hydrophobic collapse constraine d by the requirement that polar groups be either exposed to solvent or form hydrogen bonds. More generally it appears from this study that f or a folding model to be a realistic, it must properly account for the chemical nature of the polypeptide chain, particularly the solvation energetics of amide groups. (C) 1995 Academic Press Limited