Computational and Molecular Dynamics Simulation Approach To Analyze the Impact of XPD Gene Mutation on Protein Stability and Function

Abstract

AbstractXPD acts as a functional helicase and aids in unwinding double helix around damaged DNA, leading to efficient DNA repair. Mutations of XPD give rise to DNA-repair deficiency diseases and cancer proneness. In this study, cancer-causing missense mutation that could inactivate helicase function and hinder its binding with other complexes were analysed using bioinformatics approach. Rigorous computational methods were employed to understand the molecular pathogenic profile of mutation. The mutant model with the desired mutation was built with I-TASSER. GROMACS 5.0.1 was used to evaluate the effect of a mutation on protein stability and function. Of the 276 missense mutations, 64 were found to be disease-causing. Out of these 64, seven were of cancer-causing mutations. Among these, we evaluated K48R mutation in a computational simulated environment to determine its impact on protein stability and function since K48 position was ascertained to be highly conserved and substitution with arginine could impair the XPD activity. Molecular Dynamic Simulation and Essential Dynamics analysis showed that K48R mutation altered protein structural stability and produced conformational drift. Our predictions thus revealed that K48R mutation could impair the XPD helicase activity and affect its ability to repair the damaged DNA, thus augmenting the risk for cancer.