Georgetown University LogoGeorgetown University Library LogoDigitalGeorgetown Home
    • Login
    View Item 
    •   DigitalGeorgetown Home
    • Georgetown University Institutional Repository
    • Georgetown University Medical Center
    • Biomedical Graduate Education
    • Department of Biochemistry and Molecular & Cellular Biology
    • Graduate Theses and Dissertations - Biochemistry and Molecular & Cellular Biology
    • View Item
    •   DigitalGeorgetown Home
    • Georgetown University Institutional Repository
    • Georgetown University Medical Center
    • Biomedical Graduate Education
    • Department of Biochemistry and Molecular & Cellular Biology
    • Graduate Theses and Dissertations - Biochemistry and Molecular & Cellular Biology
    • View Item
    JavaScript is disabled for your browser. Some features of this site may not work without it.

    The Effect of Sequence Variation on the Essential Protein Interactions of Pathogens - a Computational Analysis

    Cover for The Effect of Sequence Variation on the Essential Protein Interactions of Pathogens - a Computational Analysis
    View/Open
    View/Open: Goodacre_georgetown_0076D_12767.pdf (4.5MB) Bookview

    Creator
    Goodacre, Norman F.
    Advisor
    Wu, Cathy
    Uetz, Peter
    Abstract
    ABSTRACT
     
    Sequence variation is investigated in two different contexts: protein domains of unknown function or DUFs, and virus-host protein-protein interactions. In Chapter I, an integrative Bioinformatics approach is used to elaborate the phylogenetic distribution, extent of structural knowledge, and size characteristics of DUFs, as well as to infer essentiality and possible functions. DUFs are often found to be conserved across all kingdoms of life, although they are particularly common among bacteria, where we report 238 essential DUFs or eDUFs. Unlike non-DUFs, essentiality for DUFs does not appear to be related to conservation. Chapter II presents a methodology for investigating essential interactions of eDUFs using systematic mutation of interface residues, which we propose will aid in solving the function of eDUFs. In Chapter III, a computational pipeline for extracting essential protein-protein interactions between a virus and its host (HIV-1 - human), and identifying sequence variants in host proteins that alter interaction (hence potentially susceptibility), is developed. 45 human proteins were predicted to lose HIV-1 binding as a result of one or more variants at the predicted interaction interface. Chapter IV presents a general computational model for predicting loss of binding due to protein mutation. This more sophisticated model uses machine-learning with features from comparisons of docking simulations of wild-type and mutant complexes, for which affinity of binding (kD) has been experimentally-defined. We show that this model has a remarkably low false-positive rate, compared with commonly-used predictors. We apply the model to a set of well-characterized HIV-1 - human protein interactions with known structures, finding 12 novel sequence variants that are likely to abolish interaction. We speculate that these sequence variants may provide some degree of resistance to HIV-1, in carriers. The computational models described can be used together to iteratively refine a high-confidence set of host sequence variants with a role in susceptibility to viral disease, or indeed any disease with an altered landscape of protein interactions arising from mutations (such as cancer).
     
    Description
    Ph.D.
    Permanent Link
    http://hdl.handle.net/10822/712428
    Date Published
    2014
    Subject
    docking; DUF; HIV-1; mutation; PPI; SNP; Bioinformatics; Molecular biology; Artificial intelligence; Bioinformatics; Molecular biology; Artificial intelligence;
    Type
    thesis
    Publisher
    Georgetown University
    Extent
    171 leaves
    Collections
    • Graduate Theses and Dissertations - Biochemistry and Molecular & Cellular Biology
    Metadata
    Show full item record

    Related items

    Showing items related by title, author, creator and subject.

    • Cover for TWO APPROACHES TO THE STUDY OF PROTEIN INTERACTIONS WITH SMALL MOLECULES: (A) STRUCTURAL ANALYSIS OF PYRIDOXAL L-PHOSPHATE BINDING ENZYMES (B) PURIFICATION, RECONSTITUTION, AND DRUG-BINDING CAPABILITIES OF THE PLASMODIUM FALCIPARUM MULTIDRUG RESISTANCE PROTEIN (PfMDR1)

      TWO APPROACHES TO THE STUDY OF PROTEIN INTERACTIONS WITH SMALL MOLECULES: (A) STRUCTURAL ANALYSIS OF PYRIDOXAL L-PHOSPHATE BINDING ENZYMES (B) PURIFICATION, RECONSTITUTION, AND DRUG-BINDING CAPABILITIES OF THE PLASMODIUM FALCIPARUM MULTIDRUG RESISTANCE PROTEIN (PfMDR1) 

      Pleeter, Perri Gail (Georgetown University, 2012)
      Structural genomics initiatives are producing new protein structures at a rate that will soon
    Related Items in Google Scholar

    Georgetown University Seal
    ©2009 - 2023 Georgetown University Library
    37th & O Streets NW
    Washington DC 20057-1174
    202.687.7385
    digitalscholarship@georgetown.edu
    Accessibility
     

     

    Browse

    All of DigitalGeorgetownCommunities & CollectionsCreatorsTitlesBy Creation DateThis CollectionCreatorsTitlesBy Creation Date

    My Account

    Login

    Statistics

    View Usage Statistics

    Georgetown University Seal
    ©2009 - 2023 Georgetown University Library
    37th & O Streets NW
    Washington DC 20057-1174
    202.687.7385
    digitalscholarship@georgetown.edu
    Accessibility