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    The Tell–Tale Cardiac Thin Filament Model: An Investigation into the Dynamics of Contraction and Relaxation

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    Author
    Williams, Michael Ryan
    Issue Date
    2017
    Keywords
    Calcium Regulation
    Cardiac Thin Filament
    Enhanced Sampling Techniques
    Familial hypertrophic cardiomyopathy
    High Performance Computing
    Molecular Dynamics
    Advisor
    Schwartz, Steven D.
    
    Metadata
    Show full item record
    Publisher
    The University of Arizona.
    Rights
    Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
    Abstract
    The correct function of cardiac sarcomeric proteins allow for people to maintain quality of life. However, mutations of the cardiac sarcomeric proteins can result in remodeling of the heart which typically results in death. I present a full atomistic cardiac thin filament model that I have developed and three studies that I conducted while at the University of Arizona, while pursuing my doctoral degree in chemistry The goal was to develop the model to be able to study the effects of the mutations on the thin filament proteins. First, I present the long process of developing the model that is still evolving as new information is available. Second, I present the study of two mutants, the troponin T R92L mutant and the tropomyosin D230N mutant. Molecular dynamics was used to simulate the wild–type and mutant versions of the model which resulted in a visualization of the change of interaction between the tropomyosin and troponin, specifically at the overlap region. Third, I present the study of calcium release which is the "gatekeeper" to cardiac contraction. Steered molecular dynamics was utilized to find a previously unseen molecular mechanism that alters the rate of calcium release depending on the mutant. Fourth, I present the study of the mechanism of the tropomyosin transition across the actin filament, in which a longitudinal transition is favored. The studies helped to provide an atomistic level understanding of the cardiac thin filament as well as the methodology to which the mutations disrupt the natural functions of the sarcomeric proteins. The new results of the research can provide new insight into how the effects of the disease causing mutations can be mitigated, potentially extending the life of people with the conditions.
    Type
    text
    Electronic Dissertation
    Degree Name
    Ph.D.
    Degree Level
    doctoral
    Degree Program
    Graduate College
    Chemistry
    Degree Grantor
    University of Arizona
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