X-ray crystallographic structure of an artificial beta-sheet dimer.

Abstract

This paper describes the X-ray crystallographic structure of a designed cyclic β-sheet peptide that forms a well-defined hydrogen-bonded dimer that mimics β-sheet dimers formed by proteins. The 54-membered ring macrocyclic peptide (1a) contains molecular template and turn units that induce β-sheet structure in a heptapeptide strand that forms the dimerization interface. The X-ray crystallographic structure reveals the structures of the two “Hao” amino acids that help template the β-sheet structure and the two δ-linked ornithine turn units that link the Hao-containing template to the heptapeptide β-strand. The Hao amino acids adopt a conformation that resembles a tripeptide in a β-strand conformation, with one edge of the Hao unit presenting an alternating array of hydrogen-bond donor and acceptor groups in the same pattern as that of a tripeptide β-strand. The δ-linked ornithines adopt a conformation that resembles a hydrogen-bonded β-turn, in which the ornithine takes the place of the i+1 and i+2 residues. The dimers formed by macrocyclic β-sheet 1a resemble the dimers of many proteins, such as defensin HNP-3, the λ-Cro repressor, interleukin 8, and the ribonuclease H domain of HIV-1 reverse transcriptase. The dimers of 1a self-assemble in the solid state into a barrel-shaped trimer of dimers in which the three dimers are arranged in a triangular fashion. Molecular modeling in which one of the three dimers is removed and the remaining two dimers are aligned face-to-face provides a model of the dimers of dimers of closely related macrocyclic β-sheet peptides that were observed in solution.