Investigation of binding modes of spider toxin-human voltage-gated sodium channel subtybe 1.7

The human voltage-gated sodium channel subtype 1.7 (hNaV1.7) is an attractive target for the development of potent and selective novel analgesics. HwTx-IV, a spider derived peptide toxin with 35-residue, inhibits hNaV1.7 with high potency by influencing the kinetics and gating behaviors of the channel, kinetics refers to the control of ion channels on and off by binding to a voltage sensor domains, so it is classified as gating modifier toxins (GMTs). In this study, we study how HwTx-IV and its variant exert its inhibitory potency on hNav1.7 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 HwTx-IV and m3-HwTx-IV to hNaV1.7 is -15.00 kJ/mol and -16.2 kJ/mol, respectively, which are consistent with the experiential results(sic)hydrophobic and electrostatic interaction both are important concerns about toxin blocking ion channels:the interactions of m3-HwTx-IV-hNaV1.7 are enhanced by mutating several residues in HwTx-IV. In comparison with the other peptide toxins of NaSpTx-F1, it is found that NaSpTx-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(sic)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 hNav1.7. Communicated by Ramaswamy H. Sarma

Automated summary

HwTx-IV, a spider-derived peptide toxin, inhibits hNaV1.7 by affecting the channel's kinetics and gating behaviors, classified as gating modifier toxins. The study found that the binding free energy of HwTx-IV and its variant to hNaV1.7 is consistent with experimental results, and the interaction strength depends on specific residues and the orientation of peptide binding relative to the channel.