title: Computational design of highly selective antimicrobial peptides.
abstract: We have created a structure-selectivity database (AMPad) of frog-derived, helical antimicrobial peptides (AMPs), in which the selectivity was determined as a therapeutic index (TI), and then used the novel concept of sequence moments to study the lengthwise asymmetry of physicochemical peptide properties. We found that the cosine of the angle between two sequence moments obtained with different hydrophobicity scales, defined as the D-descriptor, identifies highly selective peptide antibiotics. We could then use this descriptor to predict TI changes after point mutations in known AMPs, and to aid the prediction of TI for de novo designed AMPs. In combination with an amino acid selectivity index, a motif regularity index and other statistical rules extracted from AMPad, the D-descriptor enabled construction of the AMP-Designer algorithm. A 23 residue, glycine-rich, peptide suggested by the algorithm was synthesized and the activity and selectivity tested. This peptide, adepantin 1, is less than 50% identical to any other AMP, has a potent antibacterial activity against the reference organism, E. coli, and has a significantly greater selectivity (TI > 200) than the best AMP present in the AMPad database (TI = 125).
authors: Department of Physics, Faculty of Science, University of Split, 21000 Split, Croatia and Department of Life Sciences, University of Trieste, 34127 Trieste, Italy. juretic@pmfst.hr
authors: Davor
authors: D
authors: Juretić
authors: Damir
authors: D
authors: Vukicević
authors: Nada
authors: N
authors: Ilić
authors: Nikolinka
authors: N
authors: Antcheva
authors: Alessandro
authors: A
authors: Tossi
mesh_terms: D000465:Algorithms; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D003198:Computer Simulation; D057225:Data Mining; D030562:Databases, Protein; D015195:Drug Design; D004912:Erythrocytes / Q000187:drug effects; D004926:Escherichia coli / Q000187:drug effects; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D008969:Molecular Sequence Data; D017433:Protein Structure, Secondary; D015203:Reproducibility of Results; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D023181:Antimicrobial Cationic Peptides