Investigation Of Binding Modes Of Spider Toxin–human Voltage-gated Sodium Channel Subtybe 1.7

The human voltage-gated sodium channel subtype 1.7(h Na V1.7)is an attractive target for the development of potent and selective novel analgesics.Hw Tx-?,a spider derived peptide toxin with 35-residue,inhibits h Na V1.7 with high potency by influencing the kinetics and gating behaviors of the channel,so it is classified as gating modifier toxins(GMTs).In this study,we study how Hw Tx-? and its variant exert its inhibitory potency on h Nav1.7 using a range of biophysical techniques including homology modelling,molecular docking,molecular dynamics simulation,and umbrella sampling.The results show that the binding free energy of Hw Tx-? and m3-Hw Tx-? to h Na V1.7 is-15.00 k J/mol and-16.2 k J/mol,respectively,which are consistent with the experiential results;hydrophobic and electrostatic interaction both are important concerns about toxin blocking ion channels:the interactions of m3-Hw Tx-?-h Na V1.7 are enhanced by mutating several residues in Hw Tx-?.In comparison with the other peptide toxins of Na Sp Tx-F1,it is found that Na Sp Tx-F1 also had a similar binding characteristic.Combined above results,it was concluded that K32,W30 and F6,K7 and A8 in N-groove were critical for the interaction strength;G1,L3,G4,I5 in the N terminus and W33,I35 in the C terminus together can determine the peptide binding orientation relative to the channel and ultimately altered the inhibitory effect.This conclusion would be useful for designing high potency peptide inhibitor for h Nav1.7...