Chirality Effects in Peptide-Based Dynamic Combinatorial Chemistry

Naturally occurring peptides are almost exclusively composed of L-amino acids, and the incorporation of D-amino acids can profoundly alter their ability to fold and self-assemble. Here we explore the effects of chirality on the formation of disulfide dynamic combinatorial libraries (DCLs) generated by short cysteine-rich peptides. Our findings consistently show that heterochiral tripeptides form more diverse DCLs than their homochiral counterparts. The most complex library appears to encompass all possible cyclic species up to 19mers. Given that each of these species exists as a mixture of parallel and antiparallel isomers, we estimate this library to contain a total of 2,045 distinct compounds-a remarkable result considering that the library generated by the analogous homochiral peptide predominantly contains two dimers. In certain situations, peptide chirality also affects the relative stability of parallel and antiparallel isomers. Taken together, these results show that small changes in peptide chirality can be dramatically amplified through the formation of cyclic species.