Oral Presentation 2014 International Biophysics Congress

Simulation studies of voltage gated sodium channels: From ion selectivity to drug targets (#108)

Ben Corry 1
  1. Research School of Biology, The Australian National University, Acton, ACT, Australia

Voltage gated sodium channels are responsible for initiating electrical signals in cells, allowing the rapid influx of Na+ in response to small depolarising signals. Mutations and aberrant expression of these proteins is related to a range of diseases linked to nerve and muscle function, such as neuropathic pain, cardiac arrhythmia and epilepsy. These channels are established targets for drugs treating these conditions, but a range of new antibiotics, insecticides, and medications for chronic pain can be envisioned if channel blocking drugs can be designed that that selectivity target channels present in different parts of the body or in different organisms.

The recent determination of the structures of a number of voltage gated sodium channels from bacteria provides an avenue for gaining a molecular level understanding of how these channels function and how they are modified by channel targeting drugs. In this talk I will describe how we have been using molecular dynamics simulations to understand two issues relating to sodium channel function. Firstly, the ability to distinguish between ion types is critical to their function, but exactly how these proteins can rapidly tell the difference between ions as similar as Na+ and K+ requires an explanation. Secondly, designing the next generation of channel blocking drugs requires an understanding of how current drugs bind to the channel and how they reach this position. We have been taking steps to addressing these issues by using a range of free energy and advanced sampling methods to analyse the detailed interactions of ions and drugs with the channel. This has enabled us to uncover (i) mechanisms employed to exclude K+ ions while passing Na+; (ii) where currently used drugs such as benzocaine and phenytoin bind to the channel and (iii) how hydrophobic drugs can pass from the lipid bilayer through lateral fenestration get into the pore.