Influence of hydrogen bonds between sidechains and cooperativity on self‐assembly of the cyclopeptides

Abstract The self‐assembly of four cyclic D,L‐octapeptides, [‐(D‐Ala‐Gln) 4 ‐], [‐(D‐Val‐Gln) 4 ‐], [‐(D‐Leu‐Gln) 4 ‐], and [‐(D‐Phe‐Gln) 4 ‐], was investigated on the theory level in detail. Based on these cyclic peptides, which contain L‐Gln residues and possess C 4 symmetry, a series of oligomers were constructed according to different stacking modes as well as interaction patterns. We employed the semiempirical molecular orbital method AM1 to optimize the structures of all the oligomers, some of which were further studied using density functional method B3PW91/6‐31G to calculate the interaction energies. The studies indicate that when these cyclopeptides aggregate to form oligomers, or even nanotubes, four more hydrogen bonds could form between the sidechains of L‐Gln residues in addition to eight hydrogen bonds formed between the backbones of adjacent two cyclic peptides, a result that would clearly affect the self‐assembling process of cyclic peptides. The main effects can be summarized as follows. First, the dimers of these cyclic peptides with C 4 symmetry are more stable than those with D 4 symmetry due to their additional H‐bonds between Gln sidechains. Second, for the self‐assembly of the cyclopeptides, there is a competition between parallel and antiparallel stacking modes in lower oligomers such as dimers. However, with an increasing degree of oligomerization, energetically there is an increased possibility for the cyclic peptides to take the parallel stacking mode in assembly. Finally, the synergetic effect of weak interactions is the fundamental driving force for cyclic peptides to form stable nanotubes. © 2005 Wiley Periodicals, Inc. Int J Quantum Chem, 2005