Computer-Aided Characterisation of Channelopathies and Ion Channel Interactions

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Abstract
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Ion channels are proteins that control the excitability of every cell. The activities of these channels are modulated by multiple factors, including their surrounding lipid environments. Mutations that disrupt these interactions underlie diseases ranging from neonatal diabetes to epilepsy and hereditary xerocytosis, yet how a single-residue change can alter channel-gating properties remains poorly understood. In this seminar, I will show how a multidisciplinary computational approach can be used to elucidate ligand interactions and ion gating in TMEM16A channels and across all potassium channel families. This approach builds on molecular dynamics (MD) simulations, incorporating coarse-grained sampling of lipid-binding sites, enhanced-sampling free-energy calculations, and FAST adaptive sampling of gating transitions. I will then describe how these methods are being extended into computer-aided drug design, including the screening of synthetic cannabinoid pore blockers. Finally, I will outline three research directions for the next phase of my group: dissecting why related channels are differentially regulated by ligands, predicting the effects of clinical mutations, and designing the next generation of channel-targeted therapeutics.

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About the Speaker
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Dr Tanadet (Will) Pipatpolkai is a Lee Kuan Yew Postdoctoral Research Fellow at Nanyang Technological University. He completed his undergraduate studies and DPhil at the University of Oxford in the Structural Biology and Computational Biology research unit, where he used molecular dynamics simulations to study lipid interactions with ion channels under the supervision of Prof. Phillip Stansfeld and Prof. Dame Frances Ashcroft. He then moved to Stockholm for postdoctoral training at KTH Royal Institute of Technology with Prof. Lucie Delemotte, applying enhanced sampling techniques to study conformational change in ion channels. His current fellowship combines multiple simulation techniques to understand ion channels, including TMEM16A and KCa modulation and links these mechanisms to functional studies and clinical diseases.