Discrepin is a 38-residue α-toxin extracted from the venom of the Venezuelan scorpion Tityus discrepans, which inhibits ionic transit in the voltage-dependent potassium channels (Kv) of A-type current. The effect of specific residues on the IC50 between Discrepine and Kv4.3, the main component of A-type currents, is known; however, the molecular details of the toxin-channel interaction are not known. In this work, we present interaction models between Discrepin (wt) and two peptide variants (V6K/D20K and K13A) on the pore-forming domain of the Kv4.3 channel obtained from homology, docking, and molecular dynamics modeling techniques. The free energy calculations in these models correspond to the order of the experimentally determined IC50 values. Our studies shed light on the role of the K13 residue as responsible for occluding the Kv4.3 selectivity filter and the importance of the V6K mutation in the approach and stabilization of toxin-channel complex interactions.Communicated by Ramaswamy H. Sarma.
Keywords: Scorpion-toxin; binding energy; homology modeling; molecular docking; molecular dynamics; voltage-gated potassium channel.