Abstract
Homology models of mammalian voltage-gated sodium (NaV) channels based on the crystal structures of the bacterial counterparts are needed to interpret the functional data on sodium channels and understand how they operate. Such models would also be invaluable in structure-based design of therapeutics for diseases involving sodium channels such as chronic pain and heart diseases. Here we construct a homology model for the pore domain of the NaV1.4 channel and use the functional data for the binding of µ-conotoxin GIIIA to NaV1.4 to validate the model. The initial poses for the NaV1.4–GIIIA complex are obtained using the HADDOCK protein docking program, which are then refined in molecular dynamics simulations. The binding mode for the final complex is shown to be in broad agreement with the available mutagenesis data. The standard binding free energy, determined from the potential of mean force calculations, is also in good agreement with the experimental value. Because the pore domains of NaV1 channels are highly homologous, the model constructed for NaV1.4 will provide an excellent template for other NaV1 channels.
Highlights
Voltage-gated sodium (NaV) channels are responsible for initiation and propagation of action potential, which is essential for the activity of excitable cells such as neurons, heart and muscle cells [1]
Binding Mode of the NaV1.4–mconotoxin GIIIA (m-GIIIA) Complex Snapshots of the NaV1.4–m-GIIIA complex obtained from docking and molecular dynamics (MD) simulations are shown in Figure 3 (A PDB file giving the coordinates of the complex structure is provided in File S2)
An initial model for the NaV1.4–m-GIIIA complex is created using HADDOCK, which is refined in MD simulations
Summary
Voltage-gated sodium (NaV) channels are responsible for initiation and propagation of action potential, which is essential for the activity of excitable cells such as neurons, heart and muscle cells [1]. In the absence of crystal structures, indirect methods such as studying the effect of mutations on ligand binding [7,8,9,10,11,12] have been the main source of information on NaV channels. Solution of the structures of the mammalian NaV channels is likely to be more difficult and may not follow soon This leaves construction of homology models from the bacterial ones as the most viable route for making progress. The bacterial NaV channels provide a reasonable scaffold for construction of homology models for the mammalian ones, and such models can be constrained and validated using the large amount of functional data that have been accumulated over several decades [1]. Initial attempts in this regard include a docking study of tetrodotoxin and anesthetics binding to the pore domain of the NaV1.4 channel [32], and an MD study of Na+/K+ selectivity in NaV1 channels [33]
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