title: Developing a comparative docking protocol for the prediction of peptide selectivity proﬁles: investigation of potassium channel toxins.
abstract: 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 K(v)1.1, K(v)1.2 and K(v)1.3. 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 K(v)1.3 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.
authors.affiliation: School of Physics, Building A28, University of Sydney, NSW 2006, Australia. poker@physics.usyd.edu.au
authors.forename: Po-Chia
authors.initials: PC
authors.lastname: Chen
authors.forename: Serdar
authors.initials: S
authors.lastname: Kuyucak
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D003198:Computer Simulation; D020916:Conotoxins / Q000737:chemistry* / Q000633:toxicity; D006860:Hydrogen Bonding; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry*; D026902:Potassium Channel Blockers / Q000737:chemistry* / Q000633:toxicity; D024642:Potassium Channels, Voltage-Gated; D011485:Protein Binding; D011487:Protein Conformation; D051381:Rats; D012604:Scorpion Venoms / Q000737:chemistry* / Q000633:toxicity; D012984:Software
chemical_list: D020916:Conotoxins; D010455:Peptides; D026902:Potassium Channel Blockers; D024642:Potassium Channels, Voltage-Gated; D012604:Scorpion Venoms