Free energies for refolding of the common beta turn into the inverse-common beta turn: simulation of the role of D/L chirality.

Quantitative estimates of the Gibbs free-energy change (delta G) for refolding of one beta-turn conformation into another would assist rational protein design. For beta-turn models, we studied a chirally representative set of nine peptides of the form CH3CO-L1-L2-NHCH3, where loop residues L1 (i + 1) and L2 (i + 2) are achiral Gly (G), L-Ala (A), or D-Ala (a). The stabilities of their common (type I) and inverse-common (type I') beta-turn conformers (GGI is the type-I GG conformer, etc.) were estimated by free-energy simulations using explicit water molecules. An alpha-hydrogen atom of a Gly residue at L1 or L2 was replaced by a methyl group by slow growth. The resulting conformers were less stable than GGI and GGI' by about 1-3 kcal/mol (delta G = 0.9 kcal/mol for AGI and aGI', 1.0 kcal/mol for GAI and GaI', 2.1 kcal/mol for aGI and AGI', and 2.8 kcal/mol for GaI and GAI'; 1 kcal = 4.18 kJ). The delta G value for simultaneous growth of one methyl group at L1 and another at L2 was the sum of the two component delta G values. The delta G values for I-->I' refolding of the common beta-turn conformer into the inverse-common beta-turn conformer ranged over 6 kcal/mol (-3.0 for aa, -1.8 for Ga, -1.1 for aG, -0.7 for Aa, 0 for GG, 0.7 for aA, 1.1 for AG, 1.8 for GA, and 3.0 for AA). Thus, replacing L-Ala by D-Ala at both L1 and L2 of a common beta turn may contribute as much as 6 kcal/mol toward its refolding as an inverse-common beta turn.