Molecular dynamics investigation of single nucleotide polymorphism-driven variations in GSTP1 phosphorylation and substrate interaction

This study evaluated the impact of the rs1695 (Ile105Val) substitution on GSTP1 structural stability, phosphorylation accessibility, and interaction with ethacrynic acid (EA), as a substrate. Molecular dynamics (MD) simulations were conducted for wild-type (WT) and Val105 mutant GSTP1 variants using the CHARMM36m force field in GROMACS. EA was docked to phosphorylated models, followed by 100 ns MD simulations comprising minimization, equilibration, and production phases. Structural and functional effects were analyzed through RMSD, RMSF, radius of gyration (Rg), solvent-accessible surface area (SASA), and MM-PBSA binding energy calculations, with PyMOL, VMD, and BIOVIA employed for visualization. Both WT and mutant GSTP1 maintained stable RMSD profiles over 100 ns. The Val105 variant displayed reduced fluctuations (RMSF) and sustained compactness (Rg:1.68-1.75 nm) with stable solvent exposure (SASA ≈105 nm²). EA binding further stabilized the mutant, although MM-PBSA analysis indicated slightly lower affinity compared to WT. Nonetheless, interaction energies remained sufficient to preserve ligand binding. Overall, the Ile105Val substitution in GSTP1 induces subtle conformational rearrangements that decrease flexibility and modestly reduce EA binding affinity while maintaining overall structural integrity. These findings provide a mechanistic basis for reduced detoxification efficiency and altered phosphorylation regulation, potentially contributing to disease susceptibility.