Autoimmune diseases affect nearly 4% of the world's population. The NIH estimates that almost 8% of the US population is affected by one of the >80 different autoimmune diseases. The voltage-gated potassium channel KV1.3 is highly expressed in activated effector memory T cells (TEM), playing a crucial role in controlling the cell's membrane potential. Because the upregulation of KV1.3 is related to autoimmune diseases such as multiple sclerosis, type 1 diabetes, and rheumatoid arthritis, KV1.3 is an attractive target for drug candidates.1 The disulfide-rich peptide toxin ShK, from a sea anemone, blocks potassium channels such as KV1.1 and KV1.3 with potencies in the picomolar range.2 Dalazatide, an ShK analogue (ShK-186),3 has completed Phase 1 clinical trials in plaque psoriasis.4 Mutational analyses have shown that Lys22 andTyr23 are critical for channel blockade, but surrounding residues such as His19, Ser20 and Arg24 also play important roles.5 Although ShK is stabilised by three disulfide bonds, NMR experiments identify conformational changes involving its functional region,6,7 thus revealing the importance of considering the intrinsic peptide dynamics in designing more selective channel blockers. Here, we explore the dynamics of ShK through long molecular dynamics simulations using different force fields, temperature and starting structures. Our in-silico results have shown that ShK in aqueous solution can sample two different conformational states involving changes in the helix 21-24, where the functional dyad Lys22-Tyr23 is found. The side chains of Lys22-Tyr23 can be close together or far apart, which may be critical in channel recognition. Molecular docking and molecular dynamics simulations of the interaction between KV1.3 and ShK imply that Lys22 is the most important for binding. Characterising the dynamics of ShK in solution is important for docking studies with the cryo-EM structure of Kv1.3.