458118 Antimicrobial Mechanism of Action of Class IIb Bacteriocins Investigated through Molecular Simulations
In the case of class IIb bacteriocins, two different peptides are required in order to exhibit bactericidal activity. It is hypothesized that, in order to function, these two peptides must form a dimer. It has been shown that class IIb bacteriocins disrupt the membrane of the target cells. However, it is unknown if they act on their own, or if they act through a receptor-mediated mechanism as has been suggested for other class II bacteriocins.
We use plantaricin EF (plnEF) as a representative class IIb bacteriocin. PlnEF is a heterodimeric bacteriocin consisting of two peptides: plantaricin E (plnE) and plantaricin F (plnF). We performed atomistic molecular dynamics (MD) simulations of these peptides in model membranes. In combination with experimental studies, we attempt to shed light on their mechanism of action. We initially studied the behavior of the peptides on the surface of the membrane . We identified the residues that facilitate peptide-peptide and peptide-membrane interactions. We also simulated various mutants of the peptides. We compared the results with the experimentally observed activity of the mutants, which allowed us to propose structure-activity relationships.
Guided by the above-detailed findings and new experimental results, we designed a possible transmembrane dimer conformation. Our simulations revealed that the peptides interact through a GxxxG motif, which is also present in most other class IIb bacteriocins. Moreover, persistently stable hydrogen bonds and cation-π interactions strengthened the association between the peptides and stabilized the dimer inside the membrane. The simulated behavior of the peptides agreed well with experimental findings and provided a better interpretation on an extensive mutational analysis . After long atomistic MD simulations, the dimer was stable and resembled the behavior of other well-characterized transmembrane helical domains that contain the GxxxG dimerization motif. Advanced sampling techniques were employed in order to explore the dimerization free energy landscape and to investigate whether these class IIb bacteriocins have the ability to induce ion transport by themselves.
We believe that our studies can shed light on the antimicrobial mechanism of action of class IIb bacteriocins and provide valuable information for the design and optimization of new antibiotic drugs.
 P.K. Kyriakou, B. Ekblad, P.E. Kristiansen, Y.N. Kaznessis, Interactions of a class IIb bacteriocin with a model lipid bilayer, investigated through molecular dynamics simulations., Biochim Biophys Acta. 1858 (2016) 824–35.
 B. Ekblad, P.K. Kyriakou, P.E. Kristiansen, C. Oppergard, Y.N. Kaznessis, J. Nissen-Meyer, Structure-Function Analysis of the Two-Peptide Bacteriocin Plantaricin EF., (under preparation).
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