Kyriakou, Panagiota2018-08-142018-08-142017-05https://hdl.handle.net/11299/199054University of Minnesota Ph.D. dissertation May 2017. Major: Chemical Engineering. Advisor: Yiannis Kaznessis. 1 computer file (PDF); xi, 135 pages.Antibiotic resistance is a global problem and poses an alarming threat to public health. Microorganisms resistant to all commercially available antibiotics have emerged, undermining the ability to fight infectious diseases. The antibiotic resistance crisis has been attributed to the overuse of antibiotics, as well as a lack of new drug development. Coordinated efforts are needed to overcome this challenge, including discovery of alternative drugs. Bacteriocins are bacteria-produced, antimicrobial peptides that are potentially powerful antibiotic drug candidates. Despite considerable scientific interest around bacteriocins, and despite their promise as potent, latent antibiotics, their everyday medical value has been negligible. In order to more effectively utilize the full potential of bacteriocins as a platform to develop new antibacterial agents, a detailed understanding of their mechanism of action is required. This mechanistic insight will offer ways to control and optimize their activity and selectivity against specific pathogens, greatly enhancing their potential for medical applications. The goal of this work is to elucidate the mechanism of action of class II bacteriocins by employing a variety of computational methods that are built around atomistic molecular dynamics simulations. First, we studied Plantaricin EF, a two-peptide class IIb bacteriocin. This bacteriocin was simulated in different environments including water, micelles, and lipid bilayers. The interaction between the two peptides that promotes dimerization, and the interaction between the dimer and the membrane were elucidated. Guided by experimental studies, a transmembrane model of the dimer embedded in the bilayer was additionally designed. Results obtained from a 1 μs long atomistic molecular dynamics simulation, demonstrated for the first time that a bacteriocin, with a narrow antimicrobial activity range, can by itself form a water (and potentially ion) permeable, toroidal pore in a lipid bilayer. This pore was characterized in detail. It is not unlikely that the mechanism of action of bacteriocins can involve poration of the membrane as well as receptor-mediation. Therefore, the interaction of a bacteriocin with its putative receptor was also examined. Lacking the structure of a receptor, we employed structure-prediction techniques in combination with docking calculations, and molecular dynamics simulations. For the first time a class II bacteriocin-receptor complex was built, setting the ground for investigating the role that receptors play in the bactericidal activity of these antimicrobial peptides. We believe that our findings could be of importance to the designing of new antibiotic agents, as it would guide the search for better bacteriocins toward peptides with improved activity and specificity, that form stable pores, increase water or ion permeability, and interact more efficiently with a receptor.enAntibioticAntimicrobial PeptideBacteriocinMechanism of actionMolecular dynamicsPoreThesis or Dissertation