Molecular dynamics simulations reveal molecular mechanisms for the gain and loss of function effects of four SCN2A variants

SCN2A gene disorders cover a wide range of medical conditions, from epileptic encephalopathies to neurodevelopmental disorders. The variants of these disorders, studied through electrophysiology, show complex behaviors that go beyond simple classification as either gain or loss of function. In our study, we simulated the biophysical effects of variants (R937C, V208E, S1336Y, and R853Q) to understand their impact. Our findings reveal that all these variants negatively affect the structural stability of the gene, with R937C being the most unstable. Specifically, R937C disrupts important charged interactions affecting sodium ion flow, while S1336Y introduces a new interaction that impacts the channels inactivation gate. Conversely, the variants V208E and R853Q, which are located in the voltage-sensing domains, have opposite effects: R853Q increases compactness and interaction, whereas V208E shows a decrease. Our computer-based method offers a scalable way to gain crucial insights into how genetic variants influence channel dysfunction and contribute to neurodevelopmental disorders. AUTHOR SUMMARYDespite numerous advancements in computational methods for predicting variant pathogenicity in the SCN2A gene, understanding the precise biophysical molecular mechanisms associated with each variant at the atomic level remains a challenge. Presently, variants are predominantly categorized as either gain or loss of function, often overlooking critical structural details associated with these variants. This study focuses on elucidating the molecular mechanisms linked to the four most common SCN2A variants using all-atom molecular dynamics simulations, employing three replicas for each system. Our findings offer insights into the potential mechanisms underlying these four variants, thereby providing explanations for the observed electrophysiological outcomes. This investigation significantly contributes to enhancing our comprehension of how SCN2A variants manifest in various diseases. It underscores the importance of unraveling the biophysical properties underlying potential disease mechanisms, which could potentially enhance diagnostic and therapeutic strategies for patients afflicted with SCN2A-related disorders.