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Title:Computational investigations into two biological processes: membrane reshaping by light-harvesting proteins in the chromatophores of purple bacteria, and oligomerization and pore formation by the Hepatitis C viroporin p7
Author(s):Chandler, Danielle
Director of Research:Schulten, Klaus J.
Doctoral Committee Member(s):Schulten, Klaus J.; Selvin, Paul R.; DeMarco, Brian L.
Department / Program:Physics
Degree Granting Institution:University of Illinois at Urbana-Champaign
Subject(s):photosynthetic bacteria
light-harvesting complexes
membrane curvature
Hepatitis C
Hepatitis C virus (HCV)
Abstract:This dissertation presents research on two different biological systems: (1) the light-harvesting proteins in the chromatophores of purple photosynthetic bacteria, and (2) the structure and function of the Hepatitis C viroporin p7. Purple photosynthetic bacteria form membranous pseudo-organelles called chromatophores which house the photosynthetic machinery. These chromatophore structures are formed out of the cytoplasmic membrane into various species-dependent shapes, such as spheres or flat lamellar folds. AFM images show that chromatophores are densely populated by the light harvesting complexes LH1 and LH2. LH1 is always found surrounding the reaction center, forming LH1-RC core complexes, which may be elliptically-shaped monomers or S-shaped dimers depending on the species of bacteria. LH2 is a small ring-shaped complex which is produced to expand the light-harvesting capacity of the chromatophore. In addition to their role in photosynthesis, the LH2 and LH1-RC proteins may also influence the overall structure of the chromatophore organelle. Molecular dynamics simulations were employed to explore the effects of LH2s and monomeric LH1-RC complexes on the shape of the surrounding membrane. It will be demonstrated that small aggregates of LH2 complexes can induce membrane curvature, but that mixtures of LH2 and LH1-RC monomers cannot. Several factors that influence the degree of curvature are identified, and the implications of these findings on chromatophore organization and morphology are discussed. Hepatitis C virus (HCV) currently affects about 2% of the world's population, is a major source of cirrhosis and cancer of the liver, and is very difficult to treat. HCV is both prolific in virion production and fast mutating, making it highly resistant to drug therapies. Therefore, the identification of novel drug targets is highly desirable. The HCV genome encodes ten different proteins, one of which is a small transmembrane protein called p7, which oligomerizes to form ion-conducting pores. The presence of functional p7 has been shown to be critical for the late stages of the viral lifecycle, making it a potential drug target. This dissertation explores several possibilities for the structure of the p7 oligomer, finding that p7 displays a preference for hexameric or heptameric arrangements in molecular dynamics simulations, but that tetramers and pentamers are also stable in simulation. These results suggest that p7 displays some plasticity in terms of its oligomerization, and that multiple oligomerization states could co-exist, though only some would form functional channels. Further investigations in to the hexameric model identified specific residues which may be involved in channel gating. Finally, the hexameric model was fitted into a 3-dimensional cryo-electron microscopy density map of a hexameric p7; simulations of that structure in DHPC and POPC lipids illustrated the flexibility of p7 in adapting to different lipid environments.
Issue Date:2012-02-01
Genre:Dissertation / Thesis
Rights Information:Copyright 2011 Danielle Chandler
Date Available in IDEALS:2012-02-01
Date Deposited:2011-12

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