The absence of novel antibiotics and widespread resistance of microbial pathogens to conventional antibiotics are two major factors that continue to spur research aimed at identifying, characterizing and derivatizing target antimicrobial peptides (APs). Cyclotides are a novel class of antimicrobial peptides (APs) that offer promising features for the development of efficient pharmaceutical therapies because of their bioavailability, stability and broad range of biological activities. The mechanism of action for the wide range of cyclotide activity is however still unknown. This interdisciplinary project uses a combination of analytical, structural biology and computational techniques to determine the mechanism of action of cyclotides.  Unconstrained molecular dynamics (MD) simulation between a representative cyclotide (kalata B1) and lipid bilayers; 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine (POPE), 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoglycerol (POPG), and 1-palmitoyl-2-oleoylphosphatidylcholine (POPC) lipids. There is preferential binding on POPE/POPG layer as opposed to POPC mainly due to stronger electrostatic interactions. Kalata B1 in the last 60 ns of the simulation remains in close contact with the lipid head groups of POPE using 5 amino acid residues (VAL, ASN, THR, GLU, TRP). This initial data suggest that these surface interactions promote peptide distribution similar to the carpet model mechanism of interaction.<br/>

Do cyclotides aggregate with lipid bilayers? Experimental and computational characterization of the interaction between cyclotide, cyclotide mimetics, and lipid bilayers

2019 Spring National Meeting

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