A C-terminally amidated analogue of ShK is a potent and selective blocker of the voltage-gated potassium channel Kv1.3

ShK, a 35-residue peptide from a sea anemone, is a potent blocker of potassium channels. Here we describe a new ShK analogue with an additional C-terminus Lys residue and amide. ShK-K-amide is a potent blocker of Kv1.3 and, in contrast to ShK and ShK-amide, is selective for Kv1.3. To understand this selectivity, we created complexes of ShK-K-amide with Kv1.3 and Kv1.1 using docking and molecular dynamics simulations, then performed umbrella sampling simulations to construct the potential of mean force of the ligand and calculate the corresponding binding free energy for the most stable configuration. The results agree well with experimental data.

► ShK is a potent blocker of potassium channels. ► A new ShK analogue with a C-terminal Lys residue and amide was designed. ► ShK-K-amide is a potent and selective blocker of Kv1.3. ► ShK-K-amide was docked with models of Kv1.3 and Kv1.1. ► Umbrella sampling simulations were used to calculate binding free energies.