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

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dc.contributor.authorBhattarai, Nisha
dc.contributor.authorMontanucci, Ludovica
dc.contributor.authorBrünger, Tobias
dc.contributor.authorPérez Palma, Eduardo
dc.contributor.authorMartin, William
dc.contributor.authorSmith, Iris
dc.contributor.authorEng, Charis
dc.contributor.authorCheng, Feixiong
dc.contributor.authorHelbig, Ingo
dc.contributor.authorMüller, Rikke
dc.contributor.authorBrunklaus, Andreas
dc.contributor.authorSchorge, Stephanie
dc.contributor.authorLal, Dennis
dc.date.accessioned2025-01-15T16:47:22Z
dc.date.available2025-01-15T16:47:22Z
dc.date.issued2024
dc.description.abstractSCN2A 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 channel’s 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.
dc.description.versionVersión Aceptada
dc.identifier.citationBhattarai, N., Montanucci, L., Brünger, T., Pérez-Palma, E., Martin, W., Smith, I. N., Eng, C., Cheng, F., Helbig, I., Møller, R. S., Brunklaus, A., Schorge, S., & Lal, D. (2024). Molecular dynamics simulations reveal molecular mechanisms for the gain and loss of function effects of fourSCN2Avariants. bioRxiv (Cold Spring Harbor Laboratory). https://doi.org/10.1101/2024.02.19.580930
dc.identifier.doihttps://doi.org/10.1101/2024.02.19.580930
dc.identifier.urihttps://hdl.handle.net/11447/9657
dc.language.isoen
dc.subjectBiophysics
dc.titleMolecular dynamics simulations reveal molecular mechanisms for the gain and loss of function effects of four SCN2A variants
dc.typeArticle
dcterms.accessRightsAcceso Abierto
dcterms.sourcebioRxiv
dspace.entity.typePublication
relation.isAuthorOfPublication31623ebd-7791-4ceb-b04c-c69d7496b40f
relation.isAuthorOfPublication.latestForDiscovery31623ebd-7791-4ceb-b04c-c69d7496b40f

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