Peptide toxins are a valuable source of highly potent ion channel inhibitors, with applications as both tool compounds and pharmaceutical leads. Unlike linear peptide toxins, disulfide-rich peptide toxins typically adopt well-defined structures in solution that do not change significantly when binding to their target.¹ This property makes them attractive for further optimization. Disulfide-rich peptides can, however, have varying degrees of dynamical behaviour in solution.^2,3 ShK and HmK are similar toxins², both from sea anemones, that have a very high affinity (nM to pM) for the voltage-gated potassium channel K_V1.3, ^2,3 inhibition of which is clinically relevant in autoimmune disease.³ Despite their similarity, HmK displays approximately 300-fold weaker binding affinity to K_V1.3 compared to ShK.^2,3 Paradoxically, HmK is more rigid – while ShK samples multiple states (consistent with NMR data),⁴ HmK shows minimal backbone movement.^2,5 To investigate this, we performed µs length molecular dynamics simulations of ShK-HmK chimeras, analysed with principal component analysis and time-independent component analysis. We were able to identify key residues responsible for this difference in dynamics, and modeled chimeric peptides that share maximal sequence similarity with ShK that also display significantly reduced dynamics. We aim to use these chimeras to help define how ShK dynamics affect its potency towards the K_V1.3 channel.