Insights into the binding mode and functional components of the analgesic-antitumour peptide from Buthus martensii Karsch to human voltage-gated sodium channel 1.7 based on dynamic simulation analysis.

Voltage-gated sodium (Nav) channels are transmembrane proteins composed of four homologous domains (DI-DIV) that play important roles in membrane excitability in neurons and muscles. Analgesic-antitumour peptide (AGAP) is a neurotoxin from the scorpion Buthus martensii Karsch, and has been shown to exert analgesic effect by binding on site 4 of human Nav1.7 (hNav1.7). Mechanistic details about this binding, however, remain unclear. To address this issue, we compared the binding modes of AGAP/AGAPW38G/AGAPW38F and the hNav1.7 voltage-sensing domain on DII (VSD2hNav1.7) using homology modeling, molecular docking, molecular dynamics simulation and steered molecular dynamics. Results revealed the key role of tryptophan at position 38 on the binding of AGAP to VSD2hNav1.7. Pivotal roles are played also by residues on the β-turn and negatively charged residues at the C-terminal. We further show that electrostatic interaction is the main contributor to the binding free energy of the complex. Agreement between our computational simulation findings and prior experimental data supports the accuracy of the described mechanism. Accordingly, these results can provide valuable information for designing potent toxin analgesics targeting hNav1.7 with high affinity.Communicated by Ramaswamy H. Sarma.