Empirical Conformational Energy Program For Peptides Research Articles

Influence of local interactions on protein structure. I. Conformational energy studies of N-acetyl-N'-methylamides of Pro-X and X-Pro dipeptides.

AbstractConformational energy calculations using an Empirical Conformational Energy Program for Peptides (ECEPP) were carried out on the N‐acetyl‐N′‐methylamides of Pro‐X, where X = Ala, Asn, Asp, Gly, Leu, Phe, Ser, and Val, and of X‐Pro, where X = Ala, Asn, Gly, and Pro. The conformational energy was minimized from starting conformations which included all combinations of low‐energy single‐residue minima and several standard bend structures. It was found that almost all resulting minima are combinations of low‐energy single‐residue minima, suggesting that intra residue interactions predominate in determining conformation. The calculations also indicate, however, that inter residue interactions can be important. In addition, librational entropy was found to influence the relative stabilities of some minima. Because of the existence of 10–100 low‐energy minima for each dipeptide, the normalized statistical weight of an individual minimum rarely exceeds 0.3, suggesting that these dipeptides have considerable conformational flexibility and exist as statistical ensembles of low‐energy structures. The propensity of each dipeptide to form bend conformations was calculated, and the results were compared with available experimental data. It was found that bends are favored in Pro‐X dipeptides because ϕPro is fixed by the pyrrolidine ring in a conformation which is frequently found in bends, but that bends are not favored in X‐Pro dipeptides because interactions between the X residue and the pyrrolidine ring restrict the X residue to conformations which are not usually found in bends.

Conformational analysis of the 20 naturally occurring amino acid residues using ECEPP.

Conformational energy calculations using ECEPP (Empirical Conformational Energy Program for Peptides) were carried out on the N-acetyl-N'-methylamides of the 20 naturally occurring amino acids. Minimum-energy conformations were located, and the relative conformational energy, librational entropy, and free energy each minimum were calculated. The effects of intrinsic torsional potentials, intramolecular hydrogen bonds, and librational entropy on relative conformational energies and locations of minima are discussed. The results are categorized most easily by use of a new conformational letter code that is introduced here.

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.