Exploring the impact of nonsynonymous SNPs of human MAPK3 gene associated with depression using computational...

Mitogen-activated protein kinase 3 (MAPK3/ERK1) is a critical component of the MAPK signaling pathway, involved in regulating cell proliferation, differentiation, and survival. Genetic variations, particularly nonsynonymous single nucleotide polymorphisms (nsSNPs), can alter the structure and function of MAPK3, potentially leading to disease. In this study, we employed a comprehensive computational approach to identify and characterize deleterious nsSNPs in the MAPK3 gene. Out of several candidates, eight nsSNPs were predicted as deleterious by multiple tools including SIFT, PolyPhen-2, MutPred2, PhD-SNP, and SNP&GO. Based on stability predictions, evolutionary conservation, and structural assessments using I-Mutant 2.0, MUpro, DynaMut, ConSurf, and Project HOPE, three high-confidence variants-A188V, R189L, and R318Q-were selected for detailed molecular dynamics (MD) simulation analyses. Over 200 ns simulations, we evaluated RMSD, RMSF, hydrogen bonding, solvent accessible surface area (SASA), principal component analysis (PCA), and free energy landscape (FEL) to assess structural dynamics. A188V exhibited dynamics highly similar to the wild-type, suggesting a minimal functional impact. In contrast, R189L showed moderate deviations, while R318Q demonstrated significant conformational fluctuations, increased SASA, reduced hydrogen bonding, and greater sampling of energetically distinct states. PCA and FEL analyses revealed that wild-type and A188V occupied restricted conformational space with stable energy basins, while R189L and R318Q accessed broader, less stable regions. This integrative analysis identifies R318Q as a potentially pathogenic variant with implications for MAPK3 dysfunction in MDD. These findings enhance our understanding of the structural impact of MAPK3 mutations and their potential contribution to major depressive disorder.