The Self-Assembled of Cyclic D,L-α-Peptide Systems: Insights Into the Structure and Energetics

Cyclic D,L-alpha-peptides are able to self-assemble to nanotubes, although the inherent reason of the stability of this kind of nanotube as well as the intrinsic driving force of self-assembly of the cyclic D,L-a-peptides still remain elusive. In this work, using several computational approaches, we investigated the structural and energy characteristics of a series of cyclo[(-L-Phe-n-Ala-)(4)] and cyclo[(-L-Ala-n-Ala-)(4)] oligomers. The results reveal that the thermodynamic stability, cooperativity, and self-assembly patterns of cyclic D,L-alpha-peptide nanotubes are mainly determined by the interactions between cross-strand side chains instead of those between backbones. For cyclo[(-L-Phe-D-Ala-)(4)] oligomers, the steric interaction between cross-strand side chains, especially the electrostatic repulsion between the phenyls in Phe residues, brings anticooperative effect into parallel stacking mode, which is responsible for the preference of self-assembling nanotube in antiparallel vs. parallel stacking orientation. Based on our results, a novel self-assembling mechanism is put forward-it is the L-L antiparallel dimer of cyclo[(-L-Phe-D-Ala-)(4)], instead of the commonly presumed monomer, that acts as the basic building block in self assembly. It explains why these cyclic peptides uniquely self-assemble to form antiparallel nanotubes. (C) 2009 Wiley Periodicals, Inc. Int J Quantum Chem 110: 1648-1659, 2010