Unifying structural signature of eukaryotic ?-helical host defense peptides.

ABSTRACT: Diversity of ?-helical host defense peptides (?HDPs) contributes to immunity against a broad spectrum of pathogens via multiple functions. Thus, resolving common structure-function relationships among ?HDPs 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 ?HDPs derived from amino acid sequence, biochemical, and three-dimensional properties of known ?HDPs. 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 ?-core signature subsumes existing physicochemical properties of ?HDPs, and converged strongly with predictions of an independent machine-learning-based classifier recognizing sequences inducing negative Gaussian curvature in target membranes. Queries using the ?-core formula identified 93% of all annotated ?HDPs in proteomic databases and retrieved all major ?HDP families. Synthesis and antimicrobial assays confirmed efficacies of predicted sequences having no previously known antimicrobial activity. The unifying ?-core signature establishes a foundational framework for discovering and understanding ?HDPs encompassing diverse structural and mechanistic variations, and affords possibilities for deterministic design of antiinfectives.

SUBMITTER: Yount NY 

PROVIDER: S-EPMC6452647 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature