Conformation and Dynamics of the Troponin I C-Terminal Domain: Combining Single-Molecule and Computational Approaches for a Disordered Protein Region

Journal of the American Chemical Society
Lauren Ann Metskas, Elizabeth Rhoades

Abstract

In recent years, single-molecule Förster resonance energy transfer (smFRET) has emerged as a critical and flexible tool in structural biology, particularly in the study of highly dynamic regions and molecular assemblies. The usefulness of smFRET can be further extended by combining it with computational approaches, marrying the coarse-grained experimental data with higher-resolution in silico calculations. Here we use smFRET to determine six pairwise distances within the intrinsically disordered C-terminal domain of the troponin I subunit (TnIC) of the cardiac troponin complex. We used published conflicting structures of TnIC as starting models for molecular dynamics simulations, which were validated through successful comparison with smFRET measurements before extracting information on conformational dynamics. We find that pairwise distances between residues fluctuate widely in silico, but simulations are generally in good agreement with longer time scale smFRET measurements after averaging across time. Finally, Monte Carlo simulations establish that the lower-energy conformers of TnIC are indeed varied, but that the highest-sampled clusters resemble the published, conflicting models. In this way, we find that the controversia...Continue Reading

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Citations

Feb 28, 2016·Archives of Biochemistry and Biophysics·Jennifer E GildaAldrin V Gomes
Jul 11, 2016·Journal of Molecular Biology·Lauren Ann Metskas, Elizabeth Rhoades
Aug 24, 2016·The Journal of Physical Chemistry. B·Eric B Gibbs, Scott A Showalter
Oct 29, 2017·Proceedings of the National Academy of Sciences of the United States of America·Kathryn P SherryDoug Barrick
Nov 9, 2019·The Journal of Biological Chemistry·Kristen M McKibben, Elizabeth Rhoades
Feb 26, 2020·Annual Review of Physical Chemistry·Lauren Ann Metskas, Elizabeth Rhoades
Aug 29, 2018·Proceedings of the National Academy of Sciences of the United States of America·Sofia Espinoza-SanchezThomas D Pollard
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Dec 3, 2016·Proceedings of the National Academy of Sciences of the United States of America·Ana M MeloElizabeth Rhoades
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Apr 29, 2019·Journal of Muscle Research and Cell Motility·Steven Marston, Juan Eiros Zamora
May 16, 2018·Journal of Molecular Biology·Anuradha MittalRohit V Pappu
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Nov 13, 2020·The Journal of Physical Chemistry Letters·Raju RegmiGabriela S Schlau-Cohen
Apr 9, 2021·Methods : a Companion to Methods in Enzymology·Jhullian J AlstonAlex S Holehouse

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