Self‐Assembly of Linear, Natural Antimicrobial Peptides: An Evolutionary Perspective

Abstract

Antimicrobial peptides are an ancient and innate system of host defence against a wide range of microbial assailants. Mechanistically, unstructured peptides undergo a secondary structure transition into amphipathic α-helices, upon contact with membrane surfaces. This leads to peptide binding and removal of the membrane components in a detergent-like manner or via self-organisation into trans-membrane pores (either barrel-stave or toroidal pore) thereby destroying the microbe. Self-assembly of antimicrobial peptides into oligomers and ultimately amyloid has been mostly examined in parallel, however recent findings link diseases, such as Alzheimer's disease as an aberrant activity of a protective neuropeptide with antimicrobial activity. These self-assembled oligomers can also interact with membranes. Here, we review those antimicrobial peptides reported to selfassemble into amyloid, where supported by structural evidence. We consider their membrane activities as antimicrobial peptides and present evidence of consistent self-assembly patterns across major evolutionary groups. Trends are apparent across these groups, supporting the mounting data that self-assembly of antimicrobial peptides into amyloid should be considered as synergistic to the antimicrobial peptide response.

What can AlphaFold do for antimicrobial amyloids?

“…The fibril is composed of four-helix bundles with a hydrophobic core that are further assembled through a network of polar interactions. 17 To evaluate the predictive ability of AF2-ColabFold for this unique fibril structure, we modeled the monomer, decamer (10-mer), eicosamer (20-mer), and 30-mer LL37 (17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29).…”

“…Antimicrobial peptides (AMPs) play a critical role in the immune system of organisms across all kingdoms of life and are the first line of defense against pathogens 1 . AMPs often self‐assemble and some form ordered supramolecular structures that resemble amyloids 2–21 . Amyloids vary in sequence, length, composition, and function, and are secreted by organisms from all kingdoms of life.…”

Anti-Salmonella Activity of a Novel Peptide, KGGDLGLFEPTL, Derived from Egg Yolk Hydrolysate

“…Indolicidin, a small cationic AMP with 13 amino acid residues, was reported to possess a broad spectrum against Gram-negative and -positive bacteria, protozoa, fungi, and viruses. A short chain of indolicidin confers it largely linear in structure, forming random coil structures in solution [41]. Peptides with a random coil structure are capable of inserting themselves into the outer leaflet of the model lipid bilayer [42].…”

The Molecular Mechanism of PSMα3 Aggregation: A New View

“…The expected regular cross-β fibrillar form produced by other PSMs (structural) and PSMα3’s multifaceted pathogenicity on the human body (functional) drives the motivation behind the recent curiosity about this bacterial functional amyloid. Limited, yet seminal, works have bubbled up to rationalize the observed functionalities of PSMα3 based on its structure, e.g., characterization of the monomeric state, factors stabilizing the mature fibril, − the kinetics of aggregation, − nature/location-, − length-, − structure-, , and phase-specific ,,, roles of the constituting residues in diverse functionalities of the peptide, and membrane interaction with PSMα3. , However, the nascent phase of the research is filled with contradictory observations producing inconclusive inferences on the structure of the fibrillar state, ,,,, the factors required for cytotoxicity, − ,,,− sequence/structure-encoded functional specificity, and salt concentration dependence of the structure–toxicity relationship. , The lack of a comprehensive description of the deleterious aggregation process has motivated the present study, which focuses on the switching of specific roles of the charged and the hydrophobic residues at different stages of the aggregation pathway by a comparative kinetic–thermodynamic analysis between the wild-type (WT) PSMα3 sequence and three designed variants with isoleucine to model operatively increased hydrophobicity (WT → IMT, F/V/L < I), glutamine to model lack of charge with comparable hydrophilicity (WT → QMT, D/E/K ≈ Q), and proline to model moderately less hydrophilicity with one less charged residue (WT → PMT, D > P) mutations (see Supporting Information, justification behind the modeling of noncanonical mutants, Figures S1 and S2) at a low salt concentration (see Supporting Information, rationalization behind the choice of low salt concentration).…”

“…1,2 Even the notion of a sequence/disease-independent solely prevailing and hence extensively researched unifying feature of signature cross-β mature fibrils 1,2 has recently been challenged by the identification of a novel cross-α aggregated fold of a bacterial (Staphylococcus aureus) virulent 22-residue amphipathic α-helical peptide of the phenol soluble modulin (PSM) family, PSMα3. 3 The expected regular cross-β fibrillar form produced by other PSMs (structural) 4 and PSMα3's multifaceted pathogenicity on the human body (functional) 5 drives the motivation behind the recent curiosity about this bacterial functional amyloid. Limited, yet seminal, works have bubbled up to rationalize the observed functionalities of PSMα3 based on its structure, e.g., characterization of the monomeric state, 6 factors stabilizing the mature fibril, 7−9 the kinetics of aggregation, 10−13 nature/location-, 14−16 length-, 16−19 structure-, 19,20 and phasespecific 5,15,21,22 roles of the constituting residues in diverse functionalities of the peptide, and membrane interaction with PSMα3.…”