title: Correlation between simulated physicochemical properties and hemolycity of protegrin-like antimicrobial peptides: predicting experimental toxicity.
abstract: The therapeutic, antibiotic potential of antimicrobial peptides can be prohibitively diminished because of the cytotoxicity and hemolytic profiles they exhibit. Quantifying and predicting antimicrobial peptide toxicity against host cells is thus an important goal of AMP related research. In this work, we present quantitative structure activity relationships for toxicity of protegrin-like antimicrobial peptides against human cells (epithelial and red blood cells) based on physicochemical properties, such as interaction energies and radius of gyration, calculated from molecular dynamics simulations of the peptides in aqueous solvent. The hypothesis is that physicochemical properties of peptides, as manifest by their structure and interactions in a solvent and as captured by atomistic simulations, are responsible for their toxicity against human cells. Protegrins are beta-hairpin peptides with high activity against a wide variety of microbial species, but in their native state are toxic to human cells. Sixty peptides with experimentally determined toxicities were used to develop the models. We test the resulting relationships to determine their ability to predict the toxicity of several protegrin-like peptides. The developed QSARs provide insight into the mechanism of cytotoxic action of antimicrobial peptides. In a subsequent blind test, the QSAR correctly ranked four of five protegrin analogues newly synthesized and tested for toxicity.
authors.affiliation: Department of Chemical Engineering and Materials Science, University of Minnesota, 421 Washington Avenue SE, Minneapolis, MN 55455, USA.
authors.forename: Allison A
authors.initials: AA
authors.lastname: Langham
authors.forename: Himanshu
authors.initials: H
authors.lastname: Khandelia
authors.forename: Benjamin
authors.initials: B
authors.lastname: Schuster
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Waring
authors.forename: Robert I
authors.initials: RI
authors.lastname: Lehrer
authors.forename: Yiannis N
authors.initials: YN
authors.lastname: Kaznessis
mesh_terms: D000595:Amino Acid Sequence; D023181:Antimicrobial Cationic Peptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology / Q000633:toxicity; D002584:Cervix Uteri / Q000166:cytology; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000187:drug effects*; D004912:Erythrocytes / Q000187:drug effects*; D005260:Female; D006461:Hemolysis / Q000187:drug effects*; D006801:Humans; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011237:Predictive Value of Tests; D021281:Quantitative Structure-Activity Relationship; D013696:Temperature
chemical_list: D023181:Antimicrobial Cationic Peptides