In silico prediction of structural and functional effects of the E71G mutation on GARS and its role in CMT2D and HMN5A pathogenesis.

Abstract

The GARS gene codes for glycine-aminoacyl tRNA synthetase. The E71G mutation on GARS results in Charcot-Marie-Tooth disease 2D (CMT2D) with overlapping distal hereditary motor neuropathy type 5A (HMN5A) phenotype, the pathogenesis of which is unclear. This study computationally predicted the structural and functional effects of this mutation on GARS’ interaction with its ligands in relation to CMT2D and HMN5A manifestation. The performance of four protein-protein docking software (Hex, GRAMMX, PyDock, and ClusPro) was tested. GARS ligands were identified from 10 protein databases using Cytoscape 3.4.0. Thirty-one ligands met the criteria and were selected for the study. GRAMM-X was utilized for docking simulations. The RMSD value, change in binding energy and changes in interface between wild type and native GARS were analyzed. Nineteen GARS-ligand interactions increased in stability, 10 were destabilized, and 2 were unchanged. The results indicate that several biological processes (apoptosis, autophagy, and immune response) and pathways (ubiquitin proteasome system and NGF/TrkA signaling) may be affected by the E71G mutation. This suggests that GARS is a key molecule in CMT2D and HMN5A pathogenesis. The performance of molecular dynamics simulations, confirmation of results through experimentation, and investigation of other GARS mutations is recommended. The exploration of GARS as a target for novel drugs is also suggested.