Unifying structural signature of eukaryotic α-helical host defense peptides

Diversity of α-helical host defense peptides (αHDPs) contributes to immunity against a broad spectrum of pathogens via multiple functions. Thus, resolving common structure-function relationships among αHDPs is inherently difficult, even for artificial-intelligence-based methods that seek multifactor...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS Vol. 116; no. 14; p. 6944
Main Authors: Yount, Nannette Y, Weaver, David C, Lee, Ernest Y, Lee, Michelle W, Wang, Huiyuan, Chan, Liana C, Wong, Gerard C L, Yeaman, Michael R
Format: Journal Article
Language:English
Published: United States 02.04.2019
Subjects:
Eukaryotic Cells
Pattern Recognition, Automated
Peptides - chemistry
Peptides - genetics
Protein Structure, Secondary
Sequence Analysis, Protein
antimicrobial
amphipathic
antiinfective
bioinformatics
host defense
ISSN:1091-6490, 1091-6490
Online Access:Get more information
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Summary:Diversity of α-helical host defense peptides (αHDPs) contributes to immunity against a broad spectrum of pathogens via multiple functions. Thus, resolving common structure-function relationships among αHDPs is inherently difficult, even for artificial-intelligence-based methods that seek multifactorial trends rather than foundational principles. Here, bioinformatic and pattern recognition methods were applied to identify a unifying signature of eukaryotic αHDPs derived from amino acid sequence, biochemical, and three-dimensional properties of known αHDPs. The signature formula contains a helical domain of 12 residues with a mean hydrophobic moment of 0.50 and favoring aliphatic over aromatic hydrophobes in 18-aa windows of peptides or proteins matching its semantic definition. The holistic α-core signature subsumes existing physicochemical properties of αHDPs, and converged strongly with predictions of an independent machine-learning-based classifier recognizing sequences inducing negative Gaussian curvature in target membranes. Queries using the α-core formula identified 93% of all annotated αHDPs in proteomic databases and retrieved all major αHDP families. Synthesis and antimicrobial assays confirmed efficacies of predicted sequences having no previously known antimicrobial activity. The unifying α-core signature establishes a foundational framework for discovering and understanding αHDPs encompassing diverse structural and mechanistic variations, and affords possibilities for deterministic design of antiinfectives.
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ISSN:1091-6490
1091-6490
DOI:10.1073/pnas.1819250116