**3. Potassium Channel Toxins**

Due to earlier availability of crystal structures, potassium channels have been the main focus in computational investigations of marine toxins targeting ion channels. Homology models of the voltage-gated potassium channels Kv1 can be constructed using the crystal structure of the Kv1.2 channel in a straightforward manner. As shown in Table 1, there is one-to-one correspondence among the pore domain residues, thus the models can be simply constructed using the mutator plugin in the VMD software [38]. The only important point to note in modeling of the Kv1 channels is the residue following the DM signature in the extended region, which corresponds to T449 in Shaker, Y379 in Kv1.1, V381 in Kv1.2, and H404 in Kv1.3. In both Shaker and Kv1.3 the side chain of this residue makes a cross-link with the side chain of the neighboring D residue (*i.e*., T449–D447 in Shaker and H404–D402 in Kv1.3). There is no such cross-linking in Kv1.1 because the Y379 side chain is too bulky to fit around the filter. If the models of Shaker and Kv1.3 are not properly relaxed in MD simulations, these cross-links could break, resulting in a wrong model of the channel, where the T449/H404 side chains project out of the pore. The protruding T449/H404 side chains interfere with the binding of toxins and prevent their correct docking to Shaker [64] and Kv1.3 channels [54,55].


**Table 1.** Alignment of the Shaker and rat Kv1 channel sequences depicting the differences in the turret and extended regions.

In this section we discuss binding of ShK toxin from sea anemone and *κ*-conotoxin PVIIA to Kv1 potassium channels in some detail to show that computational methods can provide accurate descriptions of the channel-toxin complexes and the energetics of their binding. These examples are chosen because of the availability of the alanine scanning mutagenesis data, which allow a direct validation of the proposed complex models. NMR structures of ShK [65] and PVIIA [66] are shown in Figure 1.

**Figure 1.** NMR structures of the ShK toxin and *κ*-conotoxin PVIIA oriented with the pore inserting lysine pointing downward. In ShK, there are three disulfide bonds (C3–C35, C12–C28, and C17–C32), and three other bonds (D5–K30, K18–R24 and T6–F27), which make the structure very stable. In PVIIA, there are three disulfide bonds (C1–C16, C8–C20, and C15–C26), and two other bonds (R2–K7 and Q10–N24).
