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.
| Identifer | oai:union.ndltd.org:arizona.edu/oai:arizona.openrepository.com:10150/625895 |
| Date | January 2017 |
| Creators | Williams, Michael Ryan, Williams, Michael Ryan |
| Contributors | Schwartz, Steven D., Schwartz, Steven D., Tardiff, Jil C., Monti, Oliver L.A., Huxter, Vanessa M. |
| Publisher | The University of Arizona. |
| Source Sets | University of Arizona |
| Language | en_US |
| Detected Language | English |
| Type | text, Electronic Dissertation |
| 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. |
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