Oral Presentation 2014 International Biophysics Congress

Bacterial models as tools for sodium channel mechanistic discovery (#48)

Céline Boiteux 1 , Igor Vorobyov 2 , Toby W. Allen 1
  1. School of Applied Sciences and Health Innovations Research Institute, RMIT University, Melbourne, VIC, Australia
  2. Chemistry, University of California, Davis, CA, USA

Voltage-gated sodium (Nav) channels play essential roles in electrical signalling in the nervous system and are key pharmacological targets. New Nav structures are for members of the bacterial family, NavBac, which are simpler to study, while exhibiting important features of structure and function in common with mammalian channels. We have carried out multi-microsecond fully-atomistic simulations of the bacterial NavAb channel to describe a complex multi-ion conduction mechanism and obtain insight into Na+ selectivity. The bacterial channels do not exhibit fast inactivation, but enable examination of pore-based activation and inactivation processes, known to be involved in drug modulation. We have uncovered a surprising level of conformational flexibility of the pore domain involving residues that are critical for slow inactivation, and dynamic interplay with lipids via membrane-bound fenestrations. We have also performed simulations to provide unbiased molecular-level views of the interactions of anti-epileptic and local anaesthetic drugs with the channel, leading to previously uncharacterised drug pathways and sites. These studies, using a bacterial Nav channel model, have therefore provided new insight into Nav function and inhibition processes that will assist future drug development.