Stability of cis, trans, and nonplanar peptide groups.

Conformational energy calculations using ECEPP (Empirical Conformational Energy Program for Peptides) were performed on the molecular fragment Calpha1C'ONHCalpha2, on N-methylacetamide, and on several peptide molecules including N-acetyl-N'-methylglycineamide (Gly single residue), N-acetyl-N',N'-dimethylglycine-amide, and N-acetyl-N'-methylamide dipeptides of Gly-Gly and Gly-Pro. Energy minimization was carried out with peptide groups taken in both the cis and trans conformations, and the librational entropy and conformational free energy were determined at each minimum. It was found that the instability of cis in Gly-Gly comes primarily from interactions of the Calpha1 and HCalpha1 atoms with the Calpha2 and HCalpha2 atoms, and also from avorable interactions present in the trans form which are disallowed in the cis form, and from conformational entropy. The instability of cis in Gly-Pro is much less than in Gly-Gly because unfavorable interactions of the type CalphaH-CalphaH present in the cis conformation of Gly-Gly are present in both the cis and trans forms of Gly-Pro. The instability of cis in Gly-Pro arises mainly from the change in electrostatic energy caused by the restricted rotation about the N-Calpha bond of Pro. Entropy accounts for about 0.5 kcal/mol of the instability of cis in Gly-Pro compared with about 1.5 kcal/mol in Gly-Gly. The calculated fraction (4%) of cis in Gly-pro is in good agreement with the experimental value (5%) for related peptides in nonpolar solvents. When the dihedral angle omega of the central peptide bond in these dipeptides is allowed to vary during energy minimization, the deviations from planarity are only 1-3 degrees in low-energy minima of Gly-Gly but as much as 10 degrees in Gly-Pro. A comparison of these results with calculations in which the peptide bond was held fixed in the planar trans conformation shows that conformation-dependent properties of blocked dipeptides can be represented adequately without allowing omega to vary.