Computational Study of Binding of �-Conotoxin GIIIA to Bacterial Sodium Channels Na<inf>V</inf>Ab and Na<inf>V</inf>Rh

Abstract

© 2016 American Chemical Society. Structures of several voltage-gated sodium (Na V ) channels from bacteria have been determined recently, but the same feat might not be achieved for the mammalian counterparts in the near future. Thus, at present, computational studies of the mammalian Na V channels have to be performed using homology models based on the bacterial crystal structures. A successful homology model for the mammalian Na V 1.4 channel was recently constructed using the extensive mutation data for binding of µ-conotoxin GIIIA to Na V 1.4, which was further validated through studies of binding of other µ-conotoxins and ion permeation. Understanding the similarities and differences between the bacterial and mammalian Na V channels is an important issue, and the Na V 1.4-GIIIA system provides a good opportunity for such a comparison. To this end, we study the binding of GIIIA to the bacterial channels Na V Ab and Na V Rh. The complex structures are obtained using docking and molecular dynamics simulations, and the dissociation of GIIIA is studied through umbrella sampling simulations. The results are compared to those obtained from the Na V 1.4-GIIIA system, and the differences in the binding modes arising from the changes in the selectivity filters are highlighted.