Affinity and selectivity of ShK toxin for the Kv1 potassium channels from free energy simulations.

摘要: The voltage-gated potassium channel Kv1.3 is an attractive target for treatment of autoimmune diseases. ShK toxin from sea anemone one the most potent blockers Kv1.3, and therefore its analogues have been proposed as therapeutic leads such Increasing selectivity over other Kv1 channels a major issue in this endeavor. Here we study binding to using free energy simulation methods. Homology models Kv1.1 are constructed crystal structure Kv1.2. initial poses Kv1.x-ShK complexes obtained HADDOCK, which then refined via molecular dynamics simulations. mode each complex characterized by identifying strongly interacting residues, compare well with available mutagenesis studies. For complex, potential mean force calculated umbrella sampling simulations, corresponding absolute determined. computed energies good agreement experimental data, increases confidence on model complexes. insights gained modes will be valuable development new better properties.