Poster Presentation 2014 International Biophysics Congress

The origins of ion selectivity in a bacterial sodium channel revealed by µs-long simulations (#282)

Celine Boiteux 1 , Igor Vorobyov 2 , Toby W. Allen 1 2
  1. RMIT University, Melbourne, VIC, Australia
  2. Department of Chemistry, UC Davis, Davis, CA, USA

The recent solution of X-ray structures for the bacterial channel NavAb has provided the first opportunity to study functional mechanisms of voltage-gated sodium channels at the atomic level. NavAb is reminiscent of voltage gated K+ channels but present a wider selectivity filter, lined  by the side chains of 4 glutamates, usually indicative of a calcium-selective mammalian channel. Despite this contradiction, nominal selectivity of Na+ over Ca2+ is observed experimentally, and has been proposed to arise from the ability of the channel to accommodate and efficiently conduct a specific number of charges, while the difference  between Na+ and K+ is generally attributed to the stronger affinity of carboxylate oxygens for smaller ions (high field strength). We carry out multi-μs fully-atomistic simulations, using the purpose-built Anton supercomputer, to extract representative conformations for all occupancy states of the pore and carry out Free Energy Perturbation calculations to determine the relative free energies of Na+, K+ and Ca2+ throughout the selectivity filter. We then explore the movements of multiple ions on the multi-μs timescale to construct unbiased free energy landscapes for conduction for each of the 3 ionic species.  Our simulations provide new understanding of the fundamental interactions governing selective ion conduction in sodium channels1 . 

  1. Céline Boiteux, Igor Vorobyov, and Toby W. Allen. Ion conduction and conformational flexibility of a bacterial voltage-gated sodium channel. PNAS 2014.