Insight into tetrodotoxin blockade and resistance mechanisms of Nav1.2 sodium channel by theoretical approaches

• DOI: 10.1111/cbdd.13310
• Publication Date: 2018-04-19T17:06:22Z
• Authors: Lei Xu; Dayu Li; Junjie Ding; Li Pan; Xiaoqin Ding
• Keywords: Tetrodotoxin; Docking (animal)

Na v 1.2, a member of voltage‐gated sodium channels (Na s) that are responsible for the generation and propagation action potentials along cell membrane, play vital role in process information transmission within nervous system muscle contraction, is preferentially expressed central system. As potent selective blocker s, tetrodotoxin ( TTX ) has been extensively studied biological chemical sciences, whereas detailed mechanism by which it blocks nine 1 channel subtypes remain elusive. Despite high structural similarity, metabolite 4,9‐anhydro‐ 161 times less effective toward mammalian puzzled us to ask question why such subtle variation results largely binding affinity difference. In current work, an integrated computational strategy, including homology modeling, induced fit docking, explicit‐solvent MD simulations, free energy calculations, was employed investigate conformational determinants analogs. Based on results, H‐bond interactions between C4‐ OH C9‐ outer ring carboxylates selectivity‐filter residues, cation–π interaction primary amine guanidinium Phe385 determine difference their affinities. Moreover, computationally simulations were carried out D384N E945K mutants hN 1.2‐ , rank predicted energies accordance with experimental data. These observations provide valuable model design neurotoxins 1.2 shed light blocking channels.