diagnosis journal

Voltage-gated sodium channels (Na_V) are fundamental components of the nervous system. Their dysfunction is implicated in a number of neurological disorders, such as chronic pain, making them potential targets for the treatment of such disorders. The prominence of the Na_V channels in the nervous system has been exploited by venomous animals for preying purposes, which have developed toxins that can block the Na_V channels, thereby disabling their function. Because of their potency, such toxins could provide drug leads for the treatment of neurological disorders associated with Na_V channels. However, most toxins lack selectivity for a given target Na_V channel, and improving their selectivity profile among the Na_V1 isoforms is essential for their development as drug leads. Computational methods will be very useful in the solution of such design problems, provided accurate models of the protein-ligand complex can be constructed. Using docking and molecular dynamics simulations, we have recently constructed a model for the Na_V1.4-µ-conotoxin-GIIIA complex and validated it with the ample mutational data available for this complex. Here, we use the validated Na_V1.4 model in a systematic study of binding other µ-conotoxins (PIIIA, KIIIA and BuIIIB) to Na_V1.4. The binding mode obtained for each complex is shown to be consistent with the available mutation data and binding constants. We compare the binding modes of PIIIA, KIIIA and BuIIIB to that of GIIIA and point out the similarities and differences among them. The detailed information about Na_V1.4-µ-conotoxin interactions provided here will be useful in the design of new Na_V channel blocking peptides.