Computational prioritization of deleterious human myelin protein zero gene mutations reveals structural disruption and potential myelin dysfunction through dynamic simulations and stability analysis.

The MPZ (Myelin Protein Zero) gene, located on chromosome 1q23.3, plays a crucial role in myelin sheath formation and maintenance. Mutations in the MPZ protein are linked to demyelinating neuropathies, yet the structural and functional consequences of these mutations remain unclear. This study aims to identify and analyze the impact of nonsynonymous single nucleotide polymorphisms (nsSNPs) on the structure and function of the MPZ protein using in silico approaches. Seven sequence-based predictive tools (SIFT, PANTHER, SNP&GO, Fathmm, PhD-SNP, SNAP, MetaSNP) and five structure-based tools (I-Mutant, DynaMut, CupSAT, muPRO, iStable) were used to identify harmful nsSNPs. Molecular dynamics simulations using GROMACS further evaluated the structural and conformational effects of high-risk mutations. The screening process identified G123S and N131K as high-risk mutations. Molecular dynamics simulations revealed that the G123S mutation significantly destabilizes the MPZ protein by reducing conformational flexibility and inducing compaction. Increased root mean square deviations and localized flexibility in the G123S mutant suggest potential disruption of functional dynamics. In contrast, the N131K mutation, while reducing flexibility, preserved structural similarity to the wild-type MPZ protein, indicating a milder impact. These findings suggest that nsSNP-induced structural alterations in MPZ may negatively impact protein stability and function, potentially contributing to neuropathies. Further experimental validation is necessary to confirm these computational predictions.