Substitution impact of highly conserved arginine residue at position 75 in GJB1 gene in association with X-linked Charcot–Marie-tooth disease: A computational study. (21st January 2018)

• Record Type: Journal Article
• Authors: Agrahari, Ashish Kumar; Kumar, Amit; R, Siva; Zayed, Hatem; C, George Priya Doss
• Is Part Of: Journal of theoretical biology. Volume 437(2018)
• Page Start: 305
• Page End: 317
• Publication Date: 2018-01-21
• Subjects: Charcot Marie Tooth -- GJB1 -- R75P -- R75Q -- R75W -- Molecular modeling -- Molecular Dynamics simulation; Biology -- Periodicals; Biological Science Disciplines -- Periodicals; Biology -- Periodicals; Biologie -- Périodiques; Theoretische biologie; Biology; Periodicals; 571.05
• DOI: 10.1016/j.jtbi.2017.10.028
• Languages: English
• ISSNs: 0022-5193

Abstract

Highlights: Significance of three highly conserved mutations of GJB1 gene at position 75. Investigated using MD simulation analysis. The three mutants displayed a lesser protein stability with respect to native. Mutants alter the hydrophobicity and hydrophilicity balance of ion channel. Abstract: X-linked Charcot-Marie-Tooth type 1 X (CMTX1) disease is a subtype of Charcot-Marie-Tooth (CMT), which is mainly caused by mutations in the GJB1 gene. It is also known as connexin 32 (Cx32) that leads to Schwann cell abnormalities and peripheral neuropathy. CMTX1 is considered as the second most common form of CMT disease. The aim of this study is to computationally predict the potential impact of different single amino acid substitutions at position 75 of Cx32, from arginine (R) to proline (P), glutamine (Q) and tryptophan (W). This position is known to be highly conserved among the family of connexin. To understand the structural and functional changes due to these single amino acid substitutions, we employed a homology-modeling technique to build the three-dimensional structure models for the native and mutant proteins. The protein structures were further embedded into a POPC lipid bilayer, inserted into a water box, and subjected to molecular dynamics simulation for 50 ns. Our results show that the mutants R75P, R75Q and R75W display variable structural conformation and dynamic behavior compared to the native protein. Our data proves useful in predicting the potential pathogenicity of the mutant proteins and is expected to serve as a platform for drug discovery for patients with CMT.