Uncovering the Links Between Conformational Flexibility and Function for a Bacterial Voltage-Gated Sodium Channel

Abstract

Voltage-gated sodium channels play essential roles in electrical signaling in the nervous system and are key pharmacological targets for a range of disorders. We have carried out fully-atomistic simulations on the multi-microsecond timescale to investigate sodium channel function. These simulations have produced complete unbiased free energy maps that reveal complex multi-ion conduction mechanisms for sodium (as well as potassium and calcium ions). They have also uncovered a surprising level of conformational flexibility of the channel, including concerted movements of the selectivity filter's EEEE ring sequence side chains, and significant changes in pore domain structure as a function of glutamate protonation states. We have observed asymmetrical rearrangements of the activation gate, resembling previously proposed inactivated structures, as well as helix bending involving residues critical for slow inactivation. We report how these structural changes regulate access to lipid-facing fenestrations and the binding of the local anesthetic and anticonvulsant drugs phenytoin and benzocaine, providing new insight into the molecular mechanisms of sodium channel inhibition.