Design of Proteins with Specified Thermal Properties

TL;DR

This paper introduces a cumulant expansion method for designing proteins with specific thermal stability and folding properties, predicting an optimal folding temperature and enabling creation of thermostable proteins.

Contribution

The study presents a novel cumulant-based design approach that predicts the optimal folding temperature and produces thermostable proteins, advancing protein design techniques.

Findings

Designed sequences fold rapidly near the predicted temperature T_Z

High T_Z design yields thermostable proteins

Folding simulations confirm the method's effectiveness

Abstract

We propose a new and effective means for designing stable and fast-folding polypeptide sequences using a cumulant expansion of the molecular partition function. This method is unique in that $T_{Z}$, the ``cumulant design temperature'' entered as a parameter in the design process, is predicted also to be the optimal folding temperature. The method was tested using monte-carlo folding simulations of the designed sequences, at various folding temperatures $T_{F}$. (Folding simulations were run on a cubic lattice for computational convenience, but the design process itself is lattice-independent.) Simulations confirmed that, over a wide range of $T_{Z}$, all designed sequences folded rapidly when $T_{F} \approx T_{Z}$. Additionally, highly thermostable model proteins were created simply by designing with high $T_{Z}$. The mechanism proposed in these studies provides a plausible pathway for the evolutionary design of biologically active proteins, which {\em must} fold and remain stable within a relatively narrow range of temperatures.