In-silico Investigation of SCN2A-Associated Epilepsy and Ligand Binding Affinity of NAG

Abstract

Background: Epilepsy is a neurological disorder characterized by recurrent seizures due to abnormal brain electrical activity. The SCN2A gene, which encodes sodium channels critical for neuronal signaling, is strongly implicated in epilepsy pathogenesis. This study aimed to identify and characterize the SCN2A c.69T>G variant (transcript ENST00000375437) and evaluate its impact on protein–ligand interactions using molecular docking.

Methodology: The SCN2A c.69T>G variant was retrieved from UniProt databases. The ligand N-acetyl glucosamine (NAG) was obtained from the Protein Data Bank and docked against both wild-type and mutant SCN2A proteins. Docking parameters, including hydrogen-bond interactions, interaction distances, interaction energies, refinement energy, final docking score, and RMSD_refine, were comparatively evaluated.

Results: Wild-type SCN2A formed hydrogen bonds with Asn132, Lys235, Ser229, Lys173, Asn192, and Arg177, with interaction distances ranging from 2.8–3.5 Å and energies from −1.2 to −4.5 kcal/mol. The mutant SCN2A retained interactions with Asn132, Lys235, and Ser229 but exhibited an unfavorable acceptor–acceptor interaction. The mutant showed reduced refinement energy (E_refine = −21.62 vs. −22.32 kcal/mol), a less negative final score (E_score2 = −4.92 vs. −4.99 kcal/mol), and higher RMSD_refine (1.22 vs. 1.07 Å) compared with the wild type.

Conclusion: The c.69T>G mutation adversely affected SCN2A–NAG binding affinity and conformational stability, as indicated by the comparative docking parameters. These findings provide mechanistic insights into the potential effect of the SCN2A variant on protein–ligand interactions and its possible contribution to epilepsy.