Collaborative Research: Investigating the Interplay between the Conformational and Functional Space of Membrane Proteins and the Physicochemical Properties of the Surrounding Bilay

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Biological membranes and their constituents are involved in virtually all processes vital to living organisms, including the immune response. This research investigates how several agents of the immune response combine their antimicrobial effects by interacting with each other on bacterial cell membranes. The specific agents of interest are host defense peptides and copper ions. Host defense peptides are powerful molecules that act on a broad range of pathogenic cells, including bacteria, viruses, and fungi. Copper ions, which are present in immune cells, can damage the cell membranes of bacteria by oxidizing their phospholipids. Interestingly, some host-defense peptides contain a copper-binding motif that enables them to bind copper and become metallopeptides. In this project, the PIs will develop new bio-physical and biochemical tools to investigate how host defense metallopeptides and copper ions may synergize their antimicrobial effects. This project has the potential to produce new principles that could be useful to design novel antimicrobial biomaterials. In addition, the project will include activities that engage college and pre-college students from diverse backgrounds in hands-on science and enhance their analytical skills. The PIs will leverage the interdisciplinary and collaborative nature of their research, and passion for scientific research to spike scientific interest in young students and prepare high school students for a successful transition to college. The major goal of this research is a rigorous investigation of the interplay between host defense mechanisms at biological membranes. The molecular systems of interest are membrane-interacting host defense metallopeptides and other agents of the immune response that have the potential to unify their antimicrobial effects at lipid membranes. While host defense peptides have been studied for their ability to disrupt the conformational arrangement in bacterial cell membranes, the possibility that host defense peptides and other immune agents such as copper and oxidized lipids synergize their antimicrobial effects has not been explored on a molecular level. The PIs will test this hypothesis using peptides from fish (piscidins) and ticks (ixosins). They will leverage their expertise in the characterization of membrane assemblies and harness a platform of cutting-edge biophysical techniques (solid-state NMR, neutron diffraction, surface-sensitive methods) and biological assays to obtain structure-dynamics-function information on these metallopeptides under native-like conditions. The project will focus on model membranes to accurately and precisely control membrane composition and directly relate their molecular contents to specific functional and conformational behaviors of host defense metallopeptides and their interactions with bilayers. The project will feature assays on live cells relevant to the biological context of the chosen host defense peptides to investigate the contribution of lipid oxidation to the antimicrobial potency of the peptides, identify synergistic effects among peptides, and relate biological potencies to physicochemical properties. This project will generate multiple broad impact outcomes. First, the new findings and methodologies created will contribute to advancing scientific knowledge in the fields of membrane biophysics, structural biology, immunology, and biochemistry. These fundamental principles could be useful to design novel antimicrobial agents and biomaterials. Second, the scientific environment will foster partnerships between academia and national labs. Third, the outreach activities will stimulate the interest of college and pre-college students from diverse backgrounds in hands-on science, and enhance their analytical skills.