Computational modeling and design of oligomer selective immunogens for Parkinson’s and Alzheimer’s disease
department or school: Science, Faculty of
department or school: Physics and Astronomy, Department of
data provider: DSpace
degree campus: UBCV
creator: Aina, Adekunle Kayode
issued: 2023-04-04T18:10:00Z
issued: 2023
related degree: Doctor of Philosophy - PhD
degree grantor: University of British Columbia
description: Protein aggregation-related diseases, in particular neurodegenerative diseases, are characterized by the aberrant perturbation of the underlying protein conformational ensemble. Effectively presenting epitopes using vaccines, to raise conformationally selective antibodies, is a central problem in treating neurodegenerative diseases. Parkinson’s and Alzheimer’s disease, which pathogenesis has been attributed to aberrant aggregates of alpha-synuclein and tau protein, respectively, are the two most common neurodegenerative diseases. Designing conformationally selective immunogens in silico often requires: 1.) an effective epitope scaffolding strategy that selectively targets pathologic aggregates known as oligomers while sparing the more abundant healthy monomers, with both the oligomeric and the monomeric forms having essentially identical amino acid sequences, and 2.) efficient methods and software for quantitative comparison of large conformational ensembles, which are currently not readily available. In this thesis, we apply various computational techniques including those based on information theory and principles of physics to address these two challenges. We computationally modeled and designed cyclic peptide and beta-helix protein immunogens to best mimic toxic oligomeric conformational ensembles of alpha-synuclein and tau protein computationally predicted epitopes, respectively. In both Parkinson’s and Alzheimer’s disease, our designed immunogens are predicted to be conformationally selective for toxic oligomers. Additionally, we developed a new generalized method for efficient representation and comparison of protein conformational ensembles. The method is up to 88 times faster while utilizing 48 times fewer computing cores than the readily available Encore software on a molecular dynamics-generated ensemble dataset. The methods developed and results presented in this thesis will not only accelerate the process of in silico conformation-specific immunogen des…
aggregated CHO: https://circle.library.ubc.ca/rest/handle/2429/84138
note: Computational Modeling and Designof Oligomer Selective Immunogens forParkinson’s and Alzheimer’s DiseasebyADEKUNLE KAYODE AINAB.Sc., University of Lagos, 2014M.Sc., University of Newfoundland, 2018A THESIS SUBMITTED IN PARTIAL FULFILLMENT OFTHE REQUIREMENTS FOR THE DEGREE OFDOCTOR OF PHILOSOPHYinTHE FACULTY OF GRADUATE AND POSTDOCTORAL STUDIES(PHYSICS)THE UNIVERSITY OF BRITISH COLUMBIA(Vancouver)March 2023© ADEKUNLE KAYODE AINA 2023The following individuals certify that they have read, and recommend tothe Faculty of Graduate and Postdoctoral Studies for acceptance, the thesisentitled:Computational Modeling and Design of Oligomer SelectiveImmunogens for Parkinson’s and Alzheimer’s Diseasesubmitted by Adekunle Kayode Ainain partial fulfillment of the requirements for the degree ofDoctor of Philosophy in PhysicsExamining Committee:Steven Plotkin, Professor, Physics and Astronomy, UBCSupervisorNeil Cashman, Professor, Medicine, UBCSupervisory Committee MemberJo¨rg Gsponer, Professor, Biochemistry and Molecular Biology, UBCSupervisory Committee MemberJoerg Rottler, Professor, Physics and Astronomy, UBCSupervisory Committee MemberCarl Michal, Associate Professor, Physics and Astronomy, UBCUniversity ExaminerSimcha Srebnik, Associate Professor, Chemical and Biological Engineering, UBCUniversity ExaminerJohn Straub, Professor, Chemistry, Boston University, USA)External ExamineriiAbstractProtein aggregation-related diseases, in particular neurodegenerative dis-eases, are characterized by the aberrant perturbation of the underlying pro-tein conformational ensemble. Effectively presenting epitopes using vaccines,to raise conformationally selective antibodies, is a central problem in treat-ing neurodegenerative diseases. Parkinson’s and Alzheimer’s disease, whichpathogenesis has been attributed to aberrant aggregates of α-synuclein andtau protein, respectively, are the two most common neurodegenerative dis-eases. Designing conformationally selective immunogens in silico often r…
has type: Thesis/Dissertation
date issued: 2023-05
is shown at: 10.14288/1.0429367
language: eng
degree discipline: Physics
provider: Vancouver : University of British Columbia Library
publisher: University of British Columbia
rights: Attribution-NonCommercial-NoDerivatives 4.0 International
rights URI: http://creativecommons.org/licenses/by-nc-nd/4.0/
scholar level: Graduate
contributor: Plotkin, Steven
type: Text
identifier URI: http://hdl.handle.net/2429/84138