): Gene-encoded peptide antimicrobials are ubiquitous components of host defenses in animals, including humans. They are present in epithelial surfaces and phagocytic cells, and play an important role in the initial phases of resistance to microbial invasion. These peptides are typically 20 to 40 amino acids in length, with a folded size approximating the membrane thickness. Unlike the conventional antibiotics which target protein receptors, the antimicrobial peptides act on cell's plasma membrane. While a protein has a definitive structure for recognition, a membrane is a two-dimensional molecular fluid. Thus the question arises: how do the antimicrobials distinguish species self from infectious nonself? Moreover, different antimicrobials preferentially kill different pathogens and some exhibit varying levels of lytic activity against different mammalian cells. Our goal is to elucidate the mechanism of antimicrobial peptides by studying the supramolecular structure and the energetic property of lipid bilayers containing peptides. We found that the peptides can bind to lipid bilayers in two different ways. In one (S) state, the peptides are adsorbed in the polar region of the bilayer. In another (I) state, the peptides insert transmembrane and form multiple pores, a lethal condition if occurs in cell membranes. Our hypothesis is that the condition for the transition from the S to the I state depends on the lipid composition and the chemical condition of the cell membrane, and this might explain the cell type selectivity exhibited by the antimicrobials. We will perform new experiments to investigate this hypothesis. We will conduct X-ray diffraction of the I state in both the fluid and crystalline phases with peptides labeled by heavy atoms to delineate the pore structures. We will try to describe the peptide-membrane interactions in terms of energetics. An unusual term in such interactions is the energy of bilayer deformation. We will measure the response functions of lipid bilayers to compute this energy. We will also use a new technique of inelastic X-ray scattering to study the collective dynamics of lipid molecules that might shed light on how molecules enter lipid bilayers. Finally, we will extend our study to include peptide interactions with key structural elements of bacterial membranes.
| Lee, Ming-Tao; Hung, Wei-Chin; Hsieh, Meng-Hsuan et al. (2017) Molecular State of the Membrane-Active Antibiotic Daptomycin. Biophys J 113:82-90 |
| Faust, Joseph E; Yang, Pei-Yin; Huang, Huey W (2017) Action of Antimicrobial Peptides on Bacterial and Lipid Membranes: A Direct Comparison. Biophys J 112:1663-1672 |
| Hung, Wei-Chin; Lee, Ming-Tao; Chung, Hsien et al. (2016) Comparative Study of the Condensing Effects of Ergosterol and Cholesterol. Biophys J 110:2026-33 |
| Sun, Yen; Sun, Tzu-Lin; Huang, Huey W (2016) Mode of Action of Antimicrobial Peptides on E. coli Spheroplasts. Biophys J 111:132-9 |
| Sun, Yen; Hung, Wei-Chin; Lee, Ming-Tao et al. (2015) Membrane-mediated amyloid formation of PrP 106-126: A kinetic study. Biochim Biophys Acta 1848:2422-9 |
| Faust, Joseph E; Desai, Tanvi; Verma, Avani et al. (2015) The Atlastin C-terminal tail is an amphipathic helix that perturbs the bilayer structure during endoplasmic reticulum homotypic fusion. J Biol Chem 290:4772-83 |
| Chen, Yen-Fei; Sun, Tzu-Lin; Sun, Yen et al. (2014) Interaction of daptomycin with lipid bilayers: a lipid extracting effect. Biochemistry 53:5384-92 |
| Sun, Yen; Sun, Tzu-Lin; Huang, Huey W (2014) Physical properties of Escherichia coli spheroplast membranes. Biophys J 107:2082-90 |
| Lee, Ming-Tao; Sun, Tzu-Lin; Hung, Wei-Chin et al. (2013) Process of inducing pores in membranes by melittin. Proc Natl Acad Sci U S A 110:14243-8 |
| Sun, Tzu-Lin; Sun, Yen; Lee, Chang-Chun et al. (2013) Membrane permeability of hydrocarbon-cross-linked peptides. Biophys J 104:1923-32 |
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