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Computational Studies of Cardiac and Skeletal Troponin

Troponin is a key regulatory protein in muscle contraction, consisting of three subunits troponin C (TnC), troponin I (TnI), and troponin T (TnT). Calcium association to TnC initiates contraction by causing a series of dynamic and conformational changes that allow the switch peptide of TnI to bind a...

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Autores principales: Bowman, Jacob D., Lindert, Steffen
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6696891/
https://www.ncbi.nlm.nih.gov/pubmed/31448287
http://dx.doi.org/10.3389/fmolb.2019.00068
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author Bowman, Jacob D.
Lindert, Steffen
author_facet Bowman, Jacob D.
Lindert, Steffen
author_sort Bowman, Jacob D.
collection PubMed
description Troponin is a key regulatory protein in muscle contraction, consisting of three subunits troponin C (TnC), troponin I (TnI), and troponin T (TnT). Calcium association to TnC initiates contraction by causing a series of dynamic and conformational changes that allow the switch peptide of TnI to bind and subsequently cross bridges to form between the thin and thick filament of the sarcomere. Owing to its pivotal role in contraction regulation, troponin has been the focus of numerous computational studies over the last decade. These studies elegantly supplemented a large volume of experimental work and focused on the structure, dynamics and function of the whole troponin complex, individual subunits, and even on segments of the thin filament. Molecular dynamics, Brownian dynamics, and free energy simulations have been used to elucidate the conformational dynamics and underlying free energy landscape of troponin, calcium, and switch peptide binding, as well as the effect of disease mutations, small molecules and post-translational modifications such as phosphorylation. Frequently, simulations have been used to confirm or explain experimental observations. Computer-aided drug discovery tools have been employed to identify novel potential calcium sensitizing agents binding to the TnC-TnI interface. Finally, Markov modeling has contributed to simulating contraction within the sarcomere on the mesoscale. Here we are reviewing and classifying the existing computational work on troponin and its subunits, outline current gaps in simulations elucidating troponin's role in contraction and suggest potential future developments in the field.
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spelling pubmed-66968912019-08-23 Computational Studies of Cardiac and Skeletal Troponin Bowman, Jacob D. Lindert, Steffen Front Mol Biosci Molecular Biosciences Troponin is a key regulatory protein in muscle contraction, consisting of three subunits troponin C (TnC), troponin I (TnI), and troponin T (TnT). Calcium association to TnC initiates contraction by causing a series of dynamic and conformational changes that allow the switch peptide of TnI to bind and subsequently cross bridges to form between the thin and thick filament of the sarcomere. Owing to its pivotal role in contraction regulation, troponin has been the focus of numerous computational studies over the last decade. These studies elegantly supplemented a large volume of experimental work and focused on the structure, dynamics and function of the whole troponin complex, individual subunits, and even on segments of the thin filament. Molecular dynamics, Brownian dynamics, and free energy simulations have been used to elucidate the conformational dynamics and underlying free energy landscape of troponin, calcium, and switch peptide binding, as well as the effect of disease mutations, small molecules and post-translational modifications such as phosphorylation. Frequently, simulations have been used to confirm or explain experimental observations. Computer-aided drug discovery tools have been employed to identify novel potential calcium sensitizing agents binding to the TnC-TnI interface. Finally, Markov modeling has contributed to simulating contraction within the sarcomere on the mesoscale. Here we are reviewing and classifying the existing computational work on troponin and its subunits, outline current gaps in simulations elucidating troponin's role in contraction and suggest potential future developments in the field. Frontiers Media S.A. 2019-08-09 /pmc/articles/PMC6696891/ /pubmed/31448287 http://dx.doi.org/10.3389/fmolb.2019.00068 Text en Copyright © 2019 Bowman and Lindert. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Molecular Biosciences
Bowman, Jacob D.
Lindert, Steffen
Computational Studies of Cardiac and Skeletal Troponin
title Computational Studies of Cardiac and Skeletal Troponin
title_full Computational Studies of Cardiac and Skeletal Troponin
title_fullStr Computational Studies of Cardiac and Skeletal Troponin
title_full_unstemmed Computational Studies of Cardiac and Skeletal Troponin
title_short Computational Studies of Cardiac and Skeletal Troponin
title_sort computational studies of cardiac and skeletal troponin
topic Molecular Biosciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6696891/
https://www.ncbi.nlm.nih.gov/pubmed/31448287
http://dx.doi.org/10.3389/fmolb.2019.00068
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