The Role of Key Amino Acids in the Antimicrobial Mechanism of a Bacteriocin Model Revealed by Molecular Simulations

Abstract

The AS-48 bacteriocin is a potent antimicrobial polypeptide with enhanced stability due to its circular sequence of peptidic bonds. The mechanism of biological action is still not well understood in spite of both the elucidation of the molecular structure some years ago and several experiments performed that yielded valuable information about the AS-48 bacterial membrane poration activity. In this work, we present a computational study at an atomistic scale to analyze the membrane disruption mechanism. The process is based on the two-stage model: (1) peptide binding to the bilayer surface and (2) membrane poration due to the surface tension exerted by the peptide. Indeed, the induced membrane tension mechanism is able to explain stable formation of pores leading to membrane disruption. The atomistic detail obtained from the simulations allows one to envisage the contribution of the different amino acids during the poration process. Clustering of cationic residues and hydrophobic interactions between peptide and lipids seem to be essential ingredients in the process. GLU amino acids have shown to enhance the membrane disrupting ability of the bacteriocin. TRP24–TRP24 interactions make also an important contribution in the initial stages of the poration mechanism. The detailed atomistic information obtained from the simulations can serve to better understand bacteriocin structural characteristics to design more potent antimicrobial therapies.

Characterization, mechanism and in vivo validation of Helicobacter pylori antagonism by probiotics screened from infants’ feces and oral cavity

“…Research has shown that the high amino acid content of LAB bacteriocin makes the bacteriocins positively charged at neutral or acidic pH and can be adsorbed on cation exchange columns to separate them from other heteroproteins. 73 The 0.6 mol L −1 NaCl eluted fraction of NCUH062003 showed high inhibitory activity, indicating that this fraction contained the target inhibitory proteins, which were determined by BCA analysis to have a protein concentration of 0.34 mg mL −1 (Fig. 7C).…”

Advances in the preclinical characterization of the antimicrobial peptide AS-48

“…It has a remarkable amphipathic surface where the positively charged residues (helices 4 and 5) are separated from the rest of the hydrophobic or uncharged residues (helices 1, 2, and 3) by a hypothetical plane delimitated by the Cα atoms of 4 glutamic acids (González et al, 2000;Sánchez-Hidalgo et al, 2008. This asymmetrical charge distribution, the stabilizing interaction of tryptophan residues, and the amphipathicity of the molecule play an essential role in the mechanism of action of the peptide (Cruz et al, 2021).…”

Antibacterial and Antioxidant Activity of Protein Hydrolysate Extracted from different Indonesian Avian Egg White

“…Peptides can attach to and penetrate membrane bilayers due to their amino acid composition, amphiphilicity, cationic charge, and side. Natural peptides can disrupt cytoplasmic membrane permeability, inhibit cell wall production, restrict nucleic-acid synthesis, and decrease protein synthesis, causing bacterial cell death (Cruz et al 2021).…”