Computational Study of Binding of μ-Conotoxin GIIIA (μ-CTX) to Navrh and NavAb

Abstract

Voltage gated sodium channels (Nav) are involved in several physiological activities of different cells from bacteria to mammalian. Since 2011, different crystal structures of bacterial-Nav channels have been published. Studying the interaction of toxins with bacterial-Nav channels could provide some understanding about using bacterial-Nav channels as a model of mammalian-Nav channels. Here, we studied the interaction of μ-Conotoxin-GIIIA (μ-GIIIA) with NavRh as well as with NavAb and compared the results with μ-GIIIA binding to Nav1.4.The crystal structures of NavRh (pdb id-4DXW) and NavAb (pdb id-4EKW) were embedded in a lipid bilayer and simulated for 50 ns separately.First blind docking of μ-GIIIA to pore domain of channels was done seperately using HADDDOCK to find the possible binding mode(s) and strongly interacting pairs were used in restraint docking.The best complex was selected according to the energy score. The binding pose of the toxin was transferred to a channel simulated in the membrane and the system was run for another 50 ns for stability. In NavRh, Arg-13 inserted to the pore and interacted with the S-ring while Lys11,Lys16 interacted with the E-ring while in NavAb, Lys-11 inserted to the pore and interacted with the E-ring while Arg-13, Lys-16 interacted with the surface of pore domain. The affinity of the complexes were calculated using the potential of mean force (PMF) and compared to the results for binding of μ-GIIIA to Nav1.4 which is previously done in our group.Binding modes of μ-GIIIA to bacterial channels are not similar to binding of μ-GIIIA to Nav1.4 although interacting residues of toxin are the same. PMF well depths indicate less affinity of μ-GIIIA to bacterial channels compared to Nav1.4. We conclude that bacterial Nav channels are not suitable to study human Nav channels.