Computational Analysis of the Structural and Functional Impact of the PRKN Gene Mutation (c.1130G>A) in Parkinson’s Disease

Abstract

Parkinson’s disease (PD) is a neurodegenerative disorder associated with genetic mutations, including those in the PRKN gene, which encodes the E3 ubiquitin ligase parkin. This study employed computational approaches to investigate the pathogenic effect of the PRKN G>A mutation (position 1130) and identify potential therapeutic ligands. Comprehensive Database analysis (MalaCards, DisGeNET, OMIM) identified PRKN as a key PD-associated gene with p value (P < 0.05), pathogenicity analysis (MutationTaster, FATHMM, Polyphen-2) confirmed the mutation as deleterious, while protein stability (I- I-mutant, Mu Pro) revealed protein destabilization. Molecular docking simulations demonstrated N-aryl benzimidazole enhanced binding affinity for the mutant PRKN (−7.5 kcal/mol vs. −5.5 kcal/mol in wild-type), mediated by salt bridges (GLU, GLU) and hydrophobic contacts, contrasting kinetin showed no mutation-dependent affinity changes (-5.6 kcal/mol). Protein-protein interaction networks (STRING) further implicated mutant PRKN in disrupted mitochondrial regulation. These findings highlight N-aryl benzimidazole as a promising therapeutic candidate for mutation-specific PD treatment and provide a computational framework for targeting genetic subtypes of neurodegenerative diseases.