Molecular basis of sodium channel function and modulation

Ion channels enable cellular communication, as they gate in response to external stimuli.

A theory of how energy is harnessed to support this biological function remains incomplete, in part because static structures do not provide thermodynamic insights.

Here, we propose to unravel the underpinnings of eukaryotic voltage gated sodium channels function, which are at the basis of the burst-like mechanism of electrical signal conduction in excitable cells.

To do so, we will use advanced molecular dynamics simulations, characterizing the conformational ensembles of activation and inactivation at the atomistic level, the populations of metastable states under various environmental conditions, and the pathways linking states.

The project will address three main aspects of the question: first, we will characterize the activation mechanism of the human cardiac Nav1.5 channel, adapting the enhanced sampling protocols we have established to model activation of membrane proteins.

Second, we will describe the inactivation mechanism of Nav1.5 channel by comparing the free energy of binding of the channel’s inactivation particle to possible pre-inactivated states.

Finally, we will characterize the mechanism of Nav1.5 modulation by lipids and other compounds with lipophilic properties.

This knowledge will later be exploited to guide modulation strategies, both via the design of novel modulatory scaffold, and advice on how to use known modulators to obtain a specific functional effect.