SynopsisEmpirical conformational energy calculations have been carried out on the molecule retro-all-D-methionine enkephalin. Low-energy conformers were found by energy minimization and conformational search procedures. The lowest energy conformers were found to have some stereochemical relationship to the calculated normal met-enkephalin conformers, but they were not retro-all-D-equivalent to the Met-enkephalin structures. The retro-all-D-equivalent conformations were -10 kcdmol higher energy than the low-energy conformers found here. A structural comparison between the retro-all-D-conformers and the met-enkephalin conformers shows that one cannot rely solely on topochemical analysis to predict biological activity for linear retro-all-D-peptides.

Conformational energy calculations were carried out on the molecule, somatostatin. This cyclic tetradecapeptide, first isolated from sheep and pig hypothalami, was shown to inhibit the release of growth hormone. Its sequence was determined to be NHz-Ala-Gly-Cys-Lys-Asn-Phe-PheTrp-Lys-Thr-Phe-Thr-Ser-Cys-COOH. Using a set of known conformational preferences for the individual amino acids and the condition that the disulfide bond must be closed, -lo6 randomly selected structures were generated, and those which closed the disulfide (i.e.. to -5.5 A S-S distance or less) were retained. The remaining -lo4 conformers were then examined by creating a multiplicative probability algorithm, which predicted conformers with excluded volume interactions, thus allowing the exclusion of many impossible conformations. The resulting set of -3000 allowed conformers were then treated by various stages of energy minimization, allowing only dihedral angles as variables, and a final set of -30 conformers of low energy resulted. The five lowest-energy conformations are shown.