Modulation of an Epilepsy-Causing Ion Channel by Anionic Lipids

Emad Tajkhorshid, University of Illinois at Urbana-Champaign

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Emad Tajkhorshid, Po-Chao Wen, Muyun Lihan, Zhiyu Zhao, Shashank Pant, Archit Vasan, Sepehr Dehghanighahnaviyeh, Karanpal Kapoor, Ali Rasouli, Defne Gorgun, Carlos Roberto Cuellar

Epilepsy is not one condition, but a diverse family of chronic neurological disorder characterized by abnormal and uncontrolled interruption of normal brain function, called seizures. Around 130 mutations in the gene encoding for voltage-gated potassium channel KCNQ2 have been associated with the onset of epileptic disorders. It has been proposed that the majority of these mutations mediate channel activation by disrupting the functional interactions between the channel and negatively-charged, signaling lipids, phosphatidylinositol-4,5-bisphosphate (PIP2). However, the mechanism of PIP2-mediated channel activation remains unclear. Here we propose all-atom molecular dynamics (MD) simulations coupled with enhanced sampling algorithms such as bias-exchange umbrella sampling (BEUS) to investigate the free-energy landscape of PIP2-mediated activation of KCNQ2. The proposed free-energy calculations requires large computing resources, such as the petascale platform provided by Blue Waters. This study will shed light on how specific lipid-protein interactions can affect neuronal excitability, serving as a pathophysiological mechanism underlying epileptic encephalopathy.