Speaker
Description
Ion channels play an essential role in brain communication networks. Mutations in the SCN1A gene encoding the alpha subunit of the voltage-gated sodium channel NAV1.1, expressed in the central nervous system, are responsible for severe epilepsy and migraines often resistant to treatments.
We used molecular dynamic simulations to investigate consequences of four clinically relevant SCN1A variants (R1636Q, I1498M, R859H, R946C). Structural models were generated using AlphaFold and subsequently subjected to large-scale atomistic simulations using GROMACS to characterize alterations in channel dynamics.
Our simulations revealed that the gain-of-function mutations R1636Q and I1498M exhibited a more buried IFM binding pocket and altered structural dynamics in domain IV. In contrast, the loss-of-function variant R946C displayed pronounced perturbations in the selectivity filter region. The mixed-function variant R859H showed distributed conformational changes across all four channel domains.
We further simulated the effect of the antiepileptic drugs oxcarbazepine (a sodium-channel blocker), and 8DE (a selective Nav1.1). Oxcarbazepine increased the exposure of the IFM binding pocket in both gain-of-function variants, suggesting a previously unreported mechanism that may partially restore inactivation.
Together, these results show how atomistic simulations link genetic variation to channel dynamics and drug responses, supporting variant-specific therapies in channelopathies.
