CYLINDRICAL BETA-SHEET PEPTIDE ASSEMBLIES

Recent reports have shown that cyclic peptides composed of an even num ber of alternating D- and L-amino acids can adopt flat, disklike confo rmations and stack through backbone-backbone hydrogen-bonding to form extended nanotubular structures. The present work details a general st rategy for limiting this self-assembly process through backbone alkyla tion, giving rise to cylindrical beta-sheet peptide dimers. Scope and limitations of dimerization are examined through NMR, FT-IR, mass spec tral, and X-ray crystallographic studies of 20 cyclic peptides varying in ring size, location and identity of backbone alkyl substituents, a nd amino acid composition. The cyclic peptides are shown to self-assem ble both in solution and in the solid state through the expected antip arallel beta-sheet hydrogen-bonding network. While solution dimerizati on by cyclic octapeptides appears general, peptides with alternative s maller or larger ring sizes fail to self-associate. Formation of cylin drical beta-sheet ensembles is found to tolerate a number of backbone N-alkyl substituents, including methyl, allyl, n-propyl, and pent-4-en -1-yl groups, as well as a range of amino acid side chains. Within the hemi-N-methylated octapeptide framework, residues exhibit differentia l propensities for dimer stabilization, analogous to amino acid beta-s heet propensities in natural systems. Dimer-forming cyclic D,L-peptide s are thus among the most structurally well characterized and syntheti cally accessible beta-sheet peptide model systems.