Molecular Dynamics Simulations of the Open State Structure of a Bacterial Voltage-Gated Sodium Channel Reveal the Binding Mechanisms of Channel Blockers

Abstract

Selective, rapid and transient sodium ion conduction via the opening of voltage-gated sodium channel is essential for the initiation of the action potential in excitable cells. Mutations cause malfunctions of human sodium channels, leading to a wide range of clinically detrimental and even fatal diseases, such as epilepsy, cardiac arrhythmia, and chronic pain syndrome; hence these channels are subject to extensive structural and functional studies and enlisted as key targets for drug development.Previous investigations using crystallographic, computational, and electrophysiology methods (Bagneris et al., 2014, Proc. Natl. Acad. Sci.), have shown that the affinities of selected drugs and their analogues are remarkably similar for the bacterial sodium channel NavMs and human Nav1.1 channels. Mutagenesis studies suggested two key pore-lining residues of NavMs’ S6 transmembrane helices playing pivotal roles in channel blocking; they are conserved at equivalent positions in several repeats of human Nav channels.Microsecond atomic detail equilibrium molecular dynamics simulations based on the crystal structure of an open form of NavMs (McCusker et al, 2012, Nature Comm) shed light on the mechanisms of drug interaction inside the channel cavity. The results provide atomic determinants for drug electron densities discovered in the aforementioned study. The discrepancies of binding affinities for different drug analogues are also characterized.