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Toxins 2012, 4(2), 110-138; doi:10.3390/toxins4020110

Developing a Comparative Docking Protocol for the Prediction of Peptide Selectivity Profiles: Investigation of Potassium Channel Toxins

School of Physics, Building A28, University of Sydney, NSW 2006, Australia
* Author to whom correspondence should be addressed.
Received: 16 December 2011 / Revised: 6 January 2012 / Accepted: 14 January 2012 / Published: 6 February 2012
(This article belongs to the Special Issue Animal Toxins Targeting Ion Channels Involved in Pain)
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During the development of selective peptides against highly homologous targets, a reliable tool is sought that can predict information on both mechanisms of binding and relative affinities. These tools must first be tested on known profiles before application on novel therapeutic candidates. We therefore present a comparative docking protocol in HADDOCK using critical motifs, and use it to “predict” the various selectivity profiles of several major αKTX scorpion toxin families versus Kv1.1, Kv1.2 and Kv1.3. By correlating results across toxins of similar profiles, a comprehensive set of functional residues can be identified. Reasonable models of channel-toxin interactions can be then drawn that are consistent with known affinity and mutagenesis. Without biological information on the interaction, HADDOCK reproduces mechanisms underlying the universal binding of αKTX-2 toxins, and Kv1.3 selectivity of αKTX-3 toxins. The addition of constraints encouraging the critical lysine insertion confirms these findings, and gives analogous explanations for other families, including models of partial pore-block in αKTX-6. While qualitatively informative, the HADDOCK scoring function is not yet sufficient for accurate affinity-ranking. False minima in low-affinity complexes often resemble true binding in high-affinity complexes, despite steric/conformational penalties apparent from visual inspection. This contamination significantly complicates energetic analysis, although it is usually possible to obtain correct ranking via careful interpretation of binding-well characteristics and elimination of false positives. Aside from adaptations to the broader potassium channel family, we suggest that this strategy of comparative docking can be extended to other channels of interest with known structure, especially in cases where a critical motif exists to improve docking effectiveness.
Keywords: protein-protein docking; scorpion toxins; αKv1.1;α Kv1.2; Kv1.3; selectivity; α-KTx; HADDOCK; comparative docking protein-protein docking; scorpion toxins; αKv1.1; α Kv1.2; Kv1.3; selectivity; α-KTx; HADDOCK; comparative docking
This is an open access article distributed under the Creative Commons Attribution License (CC BY 3.0).

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Chen, P.-C.; Kuyucak, S. Developing a Comparative Docking Protocol for the Prediction of Peptide Selectivity Profiles: Investigation of Potassium Channel Toxins. Toxins 2012, 4, 110-138.

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