Molecular mechanism of δ‐dendrotoxin–potassium channel recognition explored by docking and molecular dynamic simulations

δ‐Dendrotoxin, isolated from mamba snake venom, has 57 residues cross‐linked by three disulfide bridges. The protein shares a pharmacological activity with other animal toxins, the potent blockade of potassium channels, but is structurally unrelated to toxins of different species. We employed alanine‐scanning mutagenesis to explore the molecular mechanism of δ‐dendrotoxin binding to potassium channels, using protein–protein docking and molecular dynamic simulations. In our reasonable model of the δ‐dendrotoxin–ShaKv1.1 complex, δ‐dendrotoxin interacted mainly with the N‐terminal region and the turn of two antiparallel β‐sheets of the channel. This binding mode could well explain the functional roles of critical residues in δ‐dendrotoxin and the ShaKv1.1 channel. Structural analysis indicated that the critical Lys6 residue of δ‐dendrotoxin plugged its side chain into a channel selectivity filter. Another two critical δ‐dendrotoxin residues, Lys3 and Arg10, were found to contact channel residues through strong polar and nonpolar interactions, especially salt‐bridge interactions. As for the ShaKv1.1 channel, the channel turrets were found in the “half‐open state,” and two of four Glu423 in the turrets of the channel B and D chains could interact, respectively, with Lys3 and Lys26 of δ‐dendrotoxin through electrostatic interactions. The essential Asp431 channel residue was found to associate electrostatically with Arg10 of δ‐dendrotoxin, and a critical Tyr449 channel residue was just under the channel‐interacting surface of δ‐dendrotoxin. Together, these novel data may accelerate the structure‐function research of toxins in the dendrotoxin family and be of significant value in revealing the diverse interactions between animal toxins and potassium channels. Copyright © 2010 John Wiley & Sons, Ltd.