The effect of point mutations on energy conduction pathways in proteins

TL;DR

This study uses an elastic net model to identify energy-responsive residues and conduction pathways in the RyR2 protein, revealing how mutations can disrupt these pathways and potentially lead to disease.

Contribution

It introduces a simple elastic net approach to map energy conduction pathways and analyze mutation impacts in RyR2, linking structure to function and disease.

Findings

Identified a hydrogen-bonded conduction path in RyR2.

Conserved residues are located on or near this pathway.

Mutations like A77V disrupt the energy conduction pathway.

Abstract

Energetically responsive residues of the 173 amino acid N-terminal domain of the cardiac Ryanodine receptor RyR2 are identified by a simple elastic net model. Residues that respond in a correlated way to fluctuations of spatially neighboring residues specify a hydrogen bonded path through the protein. The evolutionarily conserved residues of the protein are all located on this path or in its close proximity. All of the residues of the path are either located on the two Mir domains of the protein or are hydrogen bonded them. Two calcium binding residues, E171 and E173, are proposed as potential binding region, based on insights gained from the elastic net analysis of another calcium channel receptor, the inositol 1,4,5-triphosphate receptor, IP3R. Analysis of the disease causing A77V mutated RyR2 showed that the path is disrupted by the loss of energy responsiveness of certain residues.