Stability Threshold as a Selection Principle for Protein Design

TL;DR

This paper investigates how the stability threshold influences protein design, showing that evolution-inspired optimization can produce thermodynamically stable proteins by adjusting their mutation resilience.

Contribution

It introduces an evolution-based design method that optimizes the stability threshold to ensure protein thermodynamic stability, contrasting with random heteropolymer behavior.

Findings

Random heteropolymers have zero stability threshold.

Evolution-inspired design yields a non-zero stability threshold.

Optimizing the threshold ensures thermodynamic stability.

Abstract

The sensitivity of the native states of protein-like heteropolymers to mutations modelled as perturbations in the interaction potential between amino acids is studied. The stability threshold against mutations is shown to be zero for random heteropolymers on a lattice in two dimensions, whereas a design procedure modelling evolution produces a non-zero threshold. We introduce an evolution-like protein design procedure based on an optimization of the stability threshold that is shown to naturally ensure thermodynamic stability as well.