Analysis of the Equilibrium and Kinetics of the Ankyrin Repeat Protein Myotrophin

TL;DR

This study uses a microscopic model to analyze the folding equilibrium and kinetics of Myotrophin, revealing a weakly three-state equilibrium and two-state-like kinetics, with insights into pathway differences and mutation effects.

Contribution

The paper introduces a native-centric binary variable model providing detailed microscopic insights into Myotrophin's folding behavior, aligning with experimental observations.

Findings

Weakly three-state equilibrium observed

Two-state-like folding kinetics identified

Pathway differences between folding and unfolding

Abstract

We apply the Wako-Saito-Munoz-Eaton model to the study of Myotrophin, a small ankyrin repeat protein, whose folding equilibrium and kinetics have been recently characterized experimentally. The model, which is a native-centric with binary variables, provides a finer microscopic detail than the Ising model, that has been recently applied to some different repeat proteins, while being still amenable for an exact solution. In partial agreement with the experiments, our results reveal a weakly three-state equilibrium and a two-state-like kinetics of the wild type protein despite the presence of a non-trivial free-energy profile. These features appear to be related to a careful "design" of the free-energy landscape, so that mutations can alter this picture, stabilizing some intermediates and changing the position of the rate-limiting step. Also the experimental findings of two alternative pathways, an N-terminal and a C-terminal one, are qualitatively confirmed, even if the variations in the rates upon the experimental mutations cannot be quantitatively reproduced. Interestingly, folding and unfolding pathway appear to be different, even if closely related: a property that is not generally considered in the phenomenological interpretation of the experimental data.