The Allosteric Switching Mechanism in Bacteriophage MS2

TL;DR

This study uses all-atom simulations to uncover how a specific RNA element influences conformational changes in a virus coat protein, revealing the molecular basis of allosteric regulation during virus assembly.

Contribution

It provides a detailed molecular mechanism of allosteric switching in bacteriophage MS2, highlighting the role of RNA-protein interactions and amino acid networks.

Findings

TR binding alters conformational free energy profiles

Identification of amino acid networks involved in allostery

Predictions for mutagenesis targets to modify conformational states

Abstract

In this article we use all-atom simulations to elucidate the mechanisms underlying conformational switching and allostery within the coat protein of the bacteriophage MS2. Assembly of most icosahedral virus capsids requires that the capsid protein adopt different conformations at precise locations within the capsid. It has been shown that a 19 nucleotide stem loop (TR) from the MS2 genome acts as an allosteric effector, guiding conformational switching of the coat protein during capsid assembly. Since the principal conformational changes occur far from the TR binding site, it is important to understand the molecular mechanism underlying this allosteric communication. To this end, we use all-atom simulations with explicit water combined with a path sampling technique to sample the MS2 coat protein conformational transition, in the presence and absence of TR-binding. The calculations find that TR binding strongly alters the transition free energy profile, leading to a switch in the favored conformation. We discuss changes in molecular interactions responsible for this shift. We then identify networks of amino acids with correlated motions to reveal the mechanism by which effects of TR binding span the protein. The analysis predicts amino acids whose substitution by mutagenesis could alter populations of the conformational substates or their transition rates.