The effect of aqueous solvation upon α-helix formation for polyalanines

The incremental free energies of aqueous solution for acetyl(ala) _NNH₂ in its extended unfolded and α-helical conformations are compared using the SM5.2 solvation method of Cramer and Truhlar. A combination of density functional theory (DFT) at the B3LYP/D95(d,p) and AMI has been employed using the ONIOM method. The incremental solvation energies of α-helical structures are very similar for both ONIOM and AMI optimized structures as these structures do not significantly change upon solution. However, the conformations of the unfolded peptides change from extended β-strand to polyproline II conformations upon aqueous solution. The incremental solvation free energy per residue of the polyproline II structure is about 2 kcal/mol/residue greater than that for the α-helix, representing an upper limit for the difference between the solvation energies. However, most of this difference disappears when the energy required to distort the optimized gas-phase extended β-strand structure to the optimized polyproline II solution structure is included in the analysis, leaving an estimated difference in incremental solvation free energy of 0.3-0.5 kcal/mol favoring the unfolded structure. The solution structure sacrifices the stability derived from the intramolecular C₅ H-bonds for more favorable interactions with the aqueous solvent.