Unifying structural signature of eukaryotic α-helical host defense peptides

Diversity of alpha-helical host defense peptides (alpha HDPs) contributes to immunity against a broad spectrum of pathogens via multiple functions. Thus, resolving common structure-function relationships among alpha HDPs is inherently difficult, even for artificial-intelligencebased methods that seek multifactorial trends rather than foundational principles. Here, bioinformatic and pattern recognition methods were applied to identify a unifying signature of eukaryotic alpha HDPs derived from amino acid sequence, biochemical, and three-dimensional properties of known alpha 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 alpha-core signature subsumes existing physicochemical properties of alpha 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 alpha-core formula identified 93% of all annotated alpha HDPs in proteomic databases and retrieved all major alpha HDP families. Synthesis and antimicrobial assays confirmed efficacies of predicted sequences having no previously known antimicrobial activity. The unifying alpha-core signature establishes a foundational framework for discovering and understanding alpha HDPs encompassing diverse structural and mechanistic variations, and affords possibilities for deterministic design of antiinfectives.