Time series of MM/PBSA computed enthalpy and interaction energies for PTx2–hNa_V1.7 isolated VSD II and IV systems during the all-atom molecular dynamics simulations. (A–D) Energies from PTx2 interactions with (A) deactivated VSD II, (B) activated VSD II, (C) deactivated VSD IV, and (D) activated VSD IV are displayed. The first and third columns indicate individual energy values from different replicas. The plotted values represent the moving averages calculated over intervals of 5 ns each. The second and fourth columns indicate the averaged energy values across the replicas including standard errors of the mean shown by lighter colors. The MD simulation equilibration period is shown as a light green box.