Stereochemical studies on cyclic peptides. XIII. Energy minimization studies on cyclic hexapeptides having hydrogen bonds

Abstract

The basic cyclic hexapeptide conformations which accommodate hydrogen bonded β and γ turns in the backbone have been worked out using stereochemical criteria and energy minimization procedures. It was found that cyclic hexapeptides can be made up of all possible combinations of 4±1 hydrogen bonded types I, I', II and II' β turns, giving rise to symmetric conformations having twofold and inversion symmetries as well as nonsymmetric structures. Conformations having exclusive features of 3±1 hydrogen bonded γ turns were found to be possible in threefold and S₆ symmetric cyclic hexapeptides. The results show that the cyclic hexapeptides formed by the linking of two β turn tripeptide fragments differ mainly in (a) the hydrogen bonding scheme present in the β turn tripeptides and (b) the conformation at the α-carbon atoms where the two tripeptide fragments link. The different hydrogen bonding schemes found in the component β turns are: 1) a β turn with only a 4±1 hydrogen bond, 2) a type I or I' β turn with 4±1 and 3±1 hydrogen bonds occurring in a bifurcated form and 3) a type II or II' β turn having both the 4±1 and the 3±1 hydrogen bonds with the same acceptor oxygen atom. The conformation at the linking α-carbon atoms was found to lie either in the extended region or in the 3±1 hydrogen bonded γ turn or inverse γ turn regions. Further, the threefold and the S₆ symmetric conformations have three γ turns interleaved by three extended regions or three inverse γ turns, respectively. The feasibility of accommodating alanyl residues of both isomeric forms in the CHP minima has been explored. Finally, the available experimental data are reviewed in the light of the present results.