Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.786393
Title: In silico study of mechanisms of functional modulation of cardiac myosin
Author: Hashem, S.
ISNI:       0000 0004 7971 8575
Awarding Body: Queen Mary, University of London
Current Institution: Queen Mary, University of London
Date of Award: 2019
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Abstract:
Cardiac myosin II, is an allosteric protein of great interest as it is involved in the contraction of the heart muscle. Mutations in this protein are responsible for the emergence of several cardiac diseases like hypertrophic and dilated cardiomyopathies, which can lead to heart failure and even death. Therapies based on small-molecule effectors of myosin have recently started to be explored. In particular, the myosin modulator Omecamtiv Mecarbil (OM) is currently in clinical trials for the treatment of heart failure. While the overall effect of OM is an increased contractility of the cardiac muscle, its molecular mechanism of action is still elusive. My thesis describes an in silico study of the motor domain of cardiac myosin bound to OM, where the effects of the drug on the dynamical properties of the protein are investigated for the first time with atomistic resolution using molecular dynamics simulations. Simulations were first carried out on wild type myosin in two different states of the actomyosin cycle and on mutant myosin. Myosin mutants were then investigated in order to explore whether OM would have a rescuing effect on these mutants. We found that OM increases the coupling between the structural elements of the protein, leading to a strong reduction in the amplitude of their motions. This finding is consistent with recent experimental observations that indicate an OM-induced inhibition of the power stroke. Additionally, OM was found to have long-range effects on the dynamics of distant functional regions and in particular the actin and ATP binding sites. Preliminary results from the mutant simulations also show that OM can have compensatory effects on some cardiomyopathy mutations, in agreement with recent experimental findings. The identification of the residues and the interactions mostly responsible for these effects could be used for the future development of improved drugs.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.786393  DOI: Not available
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