How Tetrodotoxin Blocks Sodium Channels: A Docking and Geometric Perspective

Voltage-gated sodium channels (VGSCs) are essential membrane proteins responsible for electrical signaling in excitable cells. Guanidinium toxins such as tetrodotoxin (TTX) and saxitoxin (STX) block these channels by binding to the extracellular pore region and have traditionally been understood to stabilize binding through multipoint electrostatic and hydrogen-bond interactions. However, the role of geometric constraints imposed by pore architecture in determining binding stability remains insufficiently characterized. Molecular docking of TTX and STX was performed under multiple grid displacement conditions, and the resulting pose ensembles were analyzed using spatial and geometric metrics. Center-of-mass clustering and distance-dependent affinity analysis revealed two distinct regimes: a deep pore region with convergent, stable poses, and an entrance region with dispersed, variable poses. Notably, the number of contact residues did not directly correlate with docking affinity, indicating that binding stability is not determined solely by anchor interactions. These results suggest that geometric convergence within sterically constrained pore regions plays a key role in stabilizing toxin binding. The rigid cage-like structures of TTX and STX appear to promote selective alignment with pore geometry, supporting a geometric constraint model of VGSC blockade.