# Chirality Effects in Peptide‐Based Dynamic Combinatorial Chemistry

## TL;DR

This study shows that mixing L- and D-amino acids in peptides increases the diversity of dynamic combinatorial libraries, which could help in drug discovery and material science.

## Contribution

The study reveals that heterochiral peptides generate significantly more diverse and complex dynamic combinatorial libraries compared to homochiral ones.

## Key findings

- Heterochiral tripeptides form DCLs with up to 2,045 distinct cyclic compounds, including parallel and antiparallel isomers.
- Homochiral peptides predominantly form only two dimeric species, highlighting the diversity boost from heterochirality.
- Peptide chirality can influence the stability of parallel and antiparallel isomers in the library.

## Abstract

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.

Heterochiral peptides are known to exhibit unique folding and self‐assembly behaviors. Yet, the impact of heterochirality in peptide‐based dynamic combinatorial chemistry remains largely unexplored. This study reveals that chirality effects can be used to increase diversity in dynamic combinatorial libraries, significantly enhancing the potential applications of these systems in the discovery of new drugs, biosensors, and adaptive materials.