Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.806556
Title: Investigating cardiomyopathies with atomistic simulations of cardiac Troponin
Author: Eiros Zamora, Juan
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2019
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Abstract:
The heart can contract and relax at an increased rate during periods of intense physical activity or stress. Through a unique regulation mechanism, the orchestrator protein of muscle contraction, Troponin, is phosphorylated. The effects of post-translational modifications of this protein are physiologically well characterised; nevertheless, there is a lack of understanding at the molecular level. This delicate regulatory mechanism can be disrupted by inherited mutations of the proteins that are involved in muscular contraction - in the heart, these are potentially fatal. Thus, an increased understanding of the disease at the molecular level is needed to develop treatments. In this work, I have employed Molecular Dynamics simulations at the microsecond timescale to investigate the structural transitions that the core domain of cardiac Troponin undergoes in aqueous solution. These simulations are a powerful complement to experimental structural biology techniques, as they provide an unrivalled level of detail at the atomic scale. Herein, I describe the effects of post-translational modifications, inherited mutations and small molecules on the structure of cardiac Troponin. We have found that the phosphorylation of S23/S24 of cTnI provokes a change in the energy landscape of WT cTn that alters the kinetics of interconversion between three major kinetic hubs by at least an order of magnitude. In the cTnC G159D mutated state, the accessed phase space is significantly reduced, as well as system-wide per-residue fluctuations. Finally, we report the binding of three lead molecules across the whole surface of cTn, and discuss the implications of the NcTnC hydrophobic patch dynamics on Calcium sensitivity.
Supervisor: Gould, Ian R. ; Marston, Steven B. Sponsor: Engineering and Physical Sciences Research Council ; La Caixa (Firm)
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.806556  DOI:
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