Modeling of the Binding of Peptide Blockers to Voltage-Gated Potassium Channels: Approaches and Evidence

Abstract

Modeling of the structure of voltage-gated potassium (KV) channels bound to peptide blockers aims to identify the key amino acid residues dictating affinity and provide insights into the toxin-channel interface. Computational approaches open up possibilities for in silico rational design of selective blockers, new molecular tools to study the cellular distribution and functional roles of potassium channels. It is anticipated that optimized blockers will advance the development of drugs that reduce over activation of potassium channels and attenuate the associated malfunction. Starting with an overview of the recent advances in computational simulation strategies to predict the bound state orientations of peptide pore blockers relative to KV-channels, we go on to review algorithms for the analysis of intermolecular interactions, and then take a look at the results of their application.

Molecular Dynamics Simulation Reveals Specific Interaction Sites between Scorpion Toxins and Kv1.2 Channel: Implications for Design of Highly Selective Drugs

“…For example, K27 of α-KTxs insert into K v channel pore region, form H-bonds with Y373, and inhibit K + pass. TVGYG motif is conservative among eukaryotic K v channel and important for binding K + [ 19 ]. Nevertheless, unconservative sites of α-KTxs interact with K v specific sites which determine the selectivity of different toxins.…”

“…Also, many simulation studies on the recognition between scorpion toxins and K + channels without a membrane have achieved good agreements with experimental data [ 53 , 58 , 59 ]. Discarding the lipid-protein interactions has also contributed to the reduction of the computational burden and the extention of the MD simulation trajectories [ 19 ]. Certainly, a transmembrane protein system could be more reliable if we take into account the membrane around the channel.…”

“…An alternative approach is to employ computative technology to solve this question. Several popular methods include homology modeling, Brownian dynamics, molecular docking, and molecular dynamics simulation [ 19 ]. Molecular dynamics simulation is a powerful tool in predicting the structures of toxin-channel complexes.…”

Molecular Simulations of Disulfide-Rich Venom Peptides with Ion Channels and Membranes

“…The level of agreement between experimental K d values and the ones calculated from the PMF varies a lot between studies highlighting the challenges involved in the accurate calculation of binding free energies for complex systems. In a recent review of K V blockers, Novoseletsky et al [ 16 ] listed a comparison of computed and experimental binding free energies for 11 peptide-channel systems. Of these, eight are within chemical accuracy of the experimental values (i.e., within 1 kcal/mol or ~4 kJ/mol).…”

“…Most simulation studies of disulfide-rich venom peptides have focused on understanding the interactions of peptides bound to voltage-gated Na V and K V channels [ 14 , 16 , 17 ] as well as ASICs [ 18 , 19 , 20 , 21 ] (see also Figure 2 ). This partially reflects the abundance of peptides that modulate these ion channels and their therapeutic potential but also the availability of high-resolution crystal structures for these proteins.…”