Theory and simulation of macromolecular crowding effects on protein folding stability and kinetics

TL;DR

This paper models how macromolecular crowding influences protein folding stability and kinetics using a self-organizing polymer model and scaled particle theory, providing predictions without adjustable parameters.

Contribution

It introduces a theoretical framework combining self-organizing polymers and scaled particle theory to predict crowding effects on protein folding.

Findings

Thermodynamics of folding described by scaled particle theory

Predictions of folding barriers and refolding rates without adjustable parameters

Effective hard sphere approximation for native, transition, and unfolded states

Abstract

We investigate the effect of macromolecular crowding on protein folding, using purely repulsive crowding particles and a self-organizing polymer model of protein folding. We find that the thermodynamics of folding for typical alpha-, beta- and alpha/beta-proteins are well described by an adaptation of the scaled particle theory (SPT). In this approach, the native state, transition state, and the unfolded protein are treated as effective hard spheres with radii approximately independent of the size and concentration of the crowders. The same model predicts the effect of crowding on the folding barrier and therefore refolding rates with no adjustable parameters. A simple extension of the SPT model, assuming additivity, can also describe the behavior of mixtures of crowding particles.