Multiple animal species have evolved resistance to the neurotoxin tetrodotoxin (TTX) through changes in voltage-gated sodium ion channels (VGSCs). Amino acid substitutions in TTX-resistant lineages appear to be positionally convergent with changes in homologous residues associated with reductions in TTX block. We used homology modeling coupled with docking simulations to test whether positionally convergent substitutions generate functional convergence at the level of TTX-channel interactions. We found little evidence that amino acids at convergent positions generated similar patterns among TTX-resistant animal lineages across several metrics, including number of polar contacts, polar contact position, and estimates of binding energy. Though binding energy values calculated for TTX docking were reduced for some TTX-resistant channels, not all TTX-resistant channels and not all of our analyses returned reduced binding energy values for TTX-resistant channels. Our results do not support a simple model of toxin resistance where a reduced number of bonds between TTX and the channel protein prevents blocking. Rather models that incorporate flexibility and movement of the protein overall may better describe how homologous substitutions in the channel cause changes in TTX block.
Keywords: TTX; convergent evolution; marine toxin; sodium channel; structure; tetrodotoxin; toxin resistance; voltage-gated ion channels.