Characterization of the coupling mechanism of scorpion β-neurotoxins on the voltage-gated sodium channel hNav1.6

Abstract

Scorpion β-neurotoxins represent a pharmacological group that affects voltage-gated sodium channels (Nav). Despite knowing the electrophysiological effect of these toxins on Nav channels, the molecular mechanism by which the union is carried out is still undetermined. In this study, computational techniques such as modeling, docking and molecular dynamics were used to elucidate the mechanism of interaction between scorpion β-neurotoxins using the neurotoxin nCssII and its recombinant variant CssII-RCR, which bind to the site-4, an extracellular receptor, of the human sodium channel hNav1.6. Different modes of interaction were observed for both toxins, where the main distinguishing feature was the interaction generated by the residue E15 on such site-4; that is, E15 in nCssII exhibits an interaction with the voltage-sensing domain II, and the same residue E15 of CssII-RCR exhibits an interaction with domain III. Despite this difference in interaction by E15, it is seen that both neurotoxins interact with similar regions of the voltage sensing domain such as the S3-S4 connecting loop (L834-E838) of the hNav1.6. Our simulations present a first approach to the mode of interaction of scorpion beta-neurotoxins in toxin-receptor complexes, being able to explain at the molecular level the phenomenon of voltage sensor entrapment generated by these toxins.

Communicated by Ramaswamy H. Sarma

Keywords:

• Scorpion-toxin
• voltage gated sodium channel
• homology modeling
• molecular docking
• molecular dynamics

Acknowledgements

We acknowledge Dirección General de Cómputo y de Tecnologías de Información y Comunicación, DGTIC-UNAM, Proyecto LANCAD-UNAM-DGTIC-376, for computer time at MIZTLI supercomputer. P.A.M-D was a PhD student from Programa de Maestrıa y Doctorado en Ciencias Bioquımicas, Universidad Nacional Autonoma de Mexico (UNAM) under a fellowship from CONACYT.

Author contributions

P.A.M-D. performed the research. G.C.B. and P.A.M-D. wrote a draft of the paper and the final version.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

P.A.M-D. is a PhD fellow from Programa de Doctorado en Ciencias Bioquímicas from Universidad Nacional Autónoma de México (UNAM) and he is supported by a PhD scholarship (CVU: 775900) from Consejo Nacional de Ciencia y Tecnología (CONACyT). Research work was funded by DGAPA-UNAM (grant number IT200321) and by CONACyT-PRONII (grant number 303045).