A multi-scale analysis of the CzrA transcription repressor highlights the allosteric changes induced by metal ion binding

TL;DR

This study investigates how zinc binding affects the structure and mechanics of the CzrA transcription repressor using molecular dynamics and a new information-theoretical analysis, revealing allosteric changes linked to metal ion coordination.

Contribution

It introduces the MEOW workflow for analyzing MD simulations to uncover allosteric regulation mechanisms in proteins, demonstrated on CzrA.

Findings

Zinc coordination alters the conformational variability of CzrA residues.

The overall protein architecture remains consistent across different zinc binding states.

MEOW effectively identifies residues critical for allosteric regulation.

Abstract

Allosteric regulation is a widespread strategy employed by several proteins to transduce chemical signals and perform biological functions. Metal sensor proteins are exemplary in this respect, e.g., in that they selectively bind and unbind DNA depending on the state of a distal ion coordination site. In this work, we carry out an investigation of the structural and mechanical properties of the CzrA transcription repressor through the analysis of microsecond-long molecular dynamics (MD) trajectories; the latter are processed through the mapping entropy optimisation workflow (MEOW), a recently developed information-theoretical method that highlights, in an unsupervised manner, residues of particular mechanical, functional, and biological importance. This approach allows us to unveil how differences in the properties of the molecule are controlled by the state of the zinc coordination site, with particular attention to the DNA binding region. These changes correlate with a redistribution of the conformational variability of the residues throughout the molecule, in spite of an overall consistency of its architecture in the two (ion-bound and free) coordination states. The results of this work corroborate previous studies, provide novel insight into the fine details of the mechanics of CzrA, and showcase the MEOW approach as a novel instrument for the study of allosteric regulation and other processes in proteins through the analysis of plain MD simulations.