# Heterochiral and Heterotypic Self-Assembly of Intrinsically Disordered Peptides Confers Peptide Supercoils with Exceptional Proteolytic Stability

## TL;DR

This paper shows that combining peptides with opposite chirality and charge can create stable, supercoiled structures that resist breakdown by enzymes.

## Contribution

The first demonstration of heterochiral and heterotypic assemblies of intrinsically disordered peptides forming supercoils with tunable proteolytic stability.

## Key findings

- Heterochiral IDP assemblies form supercoiled nanofibers when mixed in a 2:1 ratio.
- Supercoils can either protect or promote proteolysis of l-peptides depending on the d:l ratio.
- Supercoils enhance the stability of phosphotyrosine against phosphatase activity.

## Abstract

Chirality has received extensive exploration in homotypic
supramolecular
assemblies; however, few heterotypic peptide assemblies employ heterochirality,
especially in the context of intrinsically disordered peptides (IDPs).
In this work, we show that heterochiral, heterotypic assemblies of
IDPs unexpectedly form supercoils of nanofibers. Specifically, conjugating
an aromatic motif to IDPs with opposite charge and chirality results
in positively and negatively charged IDPs that form supercoils when
mixed in a 2:1 ratio. These supercoils significantly modulate the
enzymatic stability of l-peptides: they prevent the proteolysis
of l-peptides when the d-peptide to l-peptide
ratio is 2:1 but promote it when the ratio is 1:2. Moreover, the formation
of supercoils enhances the stability of post-translational modification,
phosphotyrosine, against a powerful phosphatase. This work presents
the first case of heterochiral and heterotypic assemblies of IDPs.
It offers a novel and facile approach for designing supramolecular
materials made of IDPs with tunable enzymatic stability. These materials
promise applications in a variety of in vivo settings, particularly
when efficacy depends on enzymatic stability of IDPs.