Characterizing Na+/K+ Permeation Rates through the Bacterial NavAb Sodium Channel

Leticia Stock, Vincenzo Carnevale, Werner Treptow, Michael L. Klein
2014 Biophysical Journal  
resolution structural data on human sodium channels, the publication of a number of crystal structures of related, bacterial voltage-gated sodium channel in the last 2 years has offered the opportunity to explore the mechanism of entry and location of binding sodium channel blockers. Here, molecular dynamics simulations were used to determine the binding site of two channel blockers, benzocaine and phenytoin in the bacterial channel NavAb. We find that that binding involves nonspecific
more » ... ic interaction in the channel lumen, relate this to measured binding affinities and speculate how sequence differences in this region could alter the affinity for anaesthetics. We also show the feasibility of drug entry from the membrane via the lateral fenestrations. By calculating the free energy for this process we show that these fenestrations are likely to represent the long postulated hydrophobic route of entry leading to tonic block of resting channels. While there are many differences between bacterial and human sodium channels, these results provide a first step in understanding the mechanism of action of local anaesthetics and can aid the rational search for subtype-specific drugs for use in mammalian sodium channels.
doi:10.1016/j.bpj.2013.11.774 fatcat:3ar2sq7jonccbpagth24uvtb74