Computational analysis of folding and mutation properties of C5 domain from Myosin binding protein C

TL;DR

This study uses molecular dynamics simulations and bioinformatics to analyze how specific mutations affect the folding stability and potential ligand interactions of the C5 domain in Myosin Binding Protein C, relevant to familial hypertrophic cardiomyopathy.

Contribution

It provides detailed insights into how mutations impact folding stability and suggests the role of the CD-loop in ligand binding, combining computational and bioinformatic approaches.

Findings

Asn755 mutation significantly reduces folding stability.

Arg654 and Arg668 mutations have minimal impact on folding temperature.

The CD-loop is likely natively unfolded and involved in ligand binding.

Abstract

Thermal folding Molecular Dynamics simulations of the domain C5 from Myosin Binding Protein C were performed using a native-centric model to study the role of three mutations related to Familial Hypertrophic Cardiomyopathy. Mutation of Asn755 causes the largest shift of the folding temperature, and the residue is located in the CFGA' beta-sheet featuring the highest Phi-values. The mutation thus appears to reduce the thermodynamic stability in agreement with experimental data. The mutations on Arg654 and Arg668, conversely, cause a little change in the folding temperature and they reside in the low Phi-value BDE beta-sheet, so that their pathologic role cannot be related to impairment of the folding process but possibly to the binding with target molecules. As the typical signature of Domain C5 is the presence of a longer and destabilizing CD-loop with respect to the other Ig-like domains we completed the work with a bioinformatic analysis of this loop showing a high density of negative charge and low hydrophobicity. This indicates the CD-loop as a natively unfolded sequence with a likely coupling between folding and ligand binding.