Structural modeling of peptide toxin–ion channel interactions using RosettaDock

Abstract

AbstractVoltage‐gated ion channels play essential physiological roles in action potential generation and propagation. Peptidic toxins from animal venoms target ion channels and provide useful scaffolds for the rational design of novel channel modulators with enhanced potency and subtype selectivity. Despite recent progress in obtaining experimental structures of peptide toxin–ion channel complexes, structural determination of peptide toxins bound to ion channels in physiologically important states remains challenging. Here we describe an application of RosettaDock approach to the structural modeling of peptide toxins interactions with ion channels. We tested this approach on 10 structures of peptide toxin–ion channel complexes and demonstrated that it can sample near‐native structures in all tested cases. Our approach will be useful for improving the understanding of the molecular mechanism of natural peptide toxin modulation of ion channel gating and for the structural modeling of novel peptide‐based ion channel modulators.