{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T12:15:17Z","timestamp":1790252117872,"version":"4.1.0"},"reference-count":46,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,6,22]],"date-time":"2022-06-22T00:00:00Z","timestamp":1655856000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Physiol."],"abstract":"<jats:p>Striated muscle contraction is regulated in a calcium-dependent manner through dynamic motions of the tropomyosin\/troponin polymer, a multicomponent complex wrapped around actin-containing thin filaments. Tropomyosin\/troponin sterically blocks myosin-binding at low-calcium concentrations but moves to expose myosin-binding sites at high-calcium concentrations leading to force development. Understanding the key intermolecular interactions that define these dynamic motions will promote our understanding of mutation-induced contractile dysfunction that eventually leads to hypertrophic cardiomyopathy, dilated cardiomyopathy, and skeletal myopathies. Advancements in cryoelectron microscopy (cryoEM) have resulted in a partial elucidation of structures of the thin filament, revealing many atomic-level interactions between the component proteins and critical calcium-dependent conformational alterations. However, building models at the resolutions achieved can be challenging since landmarks in the maps are often missing or ambiguous. Therefore, current computational analyses including <jats:italic>de novo<\/jats:italic> structure prediction, protein-protein docking, molecular dynamics flexible fitting, and molecular dynamics simulations are needed to ensure good quality models. We review here our efforts to model the troponin T domain spanning the head-to-tail overlap domain of tropomyosin, improving previous models. Next, we refined the published cryoEM modeled structures, which had mistakenly compressed alpha helices, with a model that has expected helical parameters while matching densities in the cryoEM volume. Lastly, we used this model to reinterpret the interactions between tropomyosin and troponin I showing key features that hold the tropomyosin cable in its low-calcium, sterically blocking position. These revised thin filament models show improved intermolecular interactions in the key low- and high-calcium regulatory states, providing novel insights into function.<\/jats:p>","DOI":"10.3389\/fphys.2022.932333","type":"journal-article","created":{"date-parts":[[2022,6,22]],"date-time":"2022-06-22T06:44:01Z","timestamp":1655880241000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":19,"title":["Modeling Human Cardiac Thin Filament Structures"],"prefix":"10.3389","volume":"13","author":[{"given":"Michael J.","family":"Rynkiewicz","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elumalai","family":"Pavadai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William","family":"Lehman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,6,22]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1763","DOI":"10.1016\/s0006-3495(97)78206-7","article-title":"Molecular Polarity in Tropomyosin-Troponin T Co-crystals","volume":"73","author":"Cabral-Lilly","year":"1997","journal-title":"Biophysical J."},{"key":"B2","doi-asserted-by":"publisher","first-page":"3794","DOI":"10.1074\/jbc.ra119.012014","article-title":"The Glutamic Acid-Rich-Long C-Terminal Extension of Troponin T Has a Critical Role in Insect Muscle Functions","volume":"295","author":"Cao","year":"2020","journal-title":"J. Biol. Chem."},{"key":"B3","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1107\/s0907444909042073","article-title":"MolProbity: All-Atom Structure Validation for Macromolecular Crystallography","volume":"66","author":"Chen","year":"2010","journal-title":"Acta Crystallogr. D. Biol. Cryst."},{"key":"B4","doi-asserted-by":"publisher","first-page":"661","DOI":"10.1007\/s00424-019-02269-0","article-title":"Moving beyond Simple Answers to Complex Disorders in Sarcomeric Cardiomyopathies: the Role of Integrated Systems","volume":"471","author":"Deranek","year":"2019","journal-title":"Pflugers Arch. - Eur. J. Physiol."},{"key":"B5","doi-asserted-by":"publisher","first-page":"821","DOI":"10.1016\/j.bpj.2020.07.006","article-title":"Cryo-EM and Molecular Docking Shows Myosin Loop 4 Contacts Actin and Tropomyosin on Thin Filaments","volume":"119","author":"Doran","year":"2020","journal-title":"Biophysical J."},{"key":"B6","doi-asserted-by":"publisher","first-page":"495","DOI":"10.1016\/0022-2836(82)90540-x","article-title":"Troponin and its Interactions with Tropomyosin","volume":"162","author":"Flicker","year":"1982","journal-title":"J. Mol. Biol."},{"key":"B7","doi-asserted-by":"publisher","first-page":"4908","DOI":"10.1021\/bi100349a","article-title":"Structure of the Tropomyosin Overlap Complex from Chicken Smooth Muscle: Insight into the Diversity of N-Terminal Recognition,","volume":"49","author":"Frye","year":"2010","journal-title":"Biochemistry"},{"key":"B8","doi-asserted-by":"publisher","first-page":"11115","DOI":"10.1073\/pnas.1710354114","article-title":"Molecular Mechanisms and Structural Features of Cardiomyopathy-Causing Troponin T Mutants in the Tropomyosin Overlap Region","volume":"114","author":"Gangadharan","year":"2017","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"B9","doi-asserted-by":"publisher","first-page":"853","DOI":"10.1152\/physrev.2000.80.2.853","article-title":"Regulation of Contraction in Striated Muscle","volume":"80","author":"Gordon","year":"2000","journal-title":"Physiol. Rev."},{"key":"B10","doi-asserted-by":"publisher","first-page":"80","DOI":"10.1016\/j.jmb.2006.08.033","article-title":"Solution NMR Structure of the Junction between Tropomyosin Molecules: Implications for Actin Binding and Regulation","volume":"364","author":"Greenfield","year":"2006","journal-title":"J. Mol. Biol."},{"key":"B11","doi-asserted-by":"publisher","first-page":"60","DOI":"10.1007\/978-0-387-85766-4_5","article-title":"Tropomyosin: Function Follows Structure","volume":"644","author":"Hitchcock-DeGregori","year":"2008","journal-title":"Adv. Exp. Med. Biol."},{"key":"B12","doi-asserted-by":"publisher","first-page":"213","DOI":"10.1007\/s10974-008-9157-6","article-title":"Gestalt-binding of Tropomyosin to Actin Filaments","volume":"29","author":"Holmes","year":"2008","journal-title":"J. Muscle Res. Cell Motil."},{"key":"B13","doi-asserted-by":"publisher","first-page":"144","DOI":"10.1016\/j.abb.2010.06.001","article-title":"Localization of the Two Tropomyosin-Binding Sites of Troponin T","volume":"500","author":"Jin","year":"2010","journal-title":"Archives Biochem. Biophysics"},{"key":"B14","doi-asserted-by":"publisher","first-page":"255","DOI":"10.1038\/nprot.2016.169","article-title":"The ClusPro Web Server for Protein-Protein Docking","volume":"12","author":"Kozakov","year":"2017","journal-title":"Nat. Protoc."},{"key":"B15","doi-asserted-by":"publisher","first-page":"1082","DOI":"10.1016\/j.bpj.2018.08.017","article-title":"Precise Binding of Tropomyosin on Actin Involves Sequence-dependent Variance in Coiled-Coil Twisting","volume":"115","author":"Lehman","year":"2018","journal-title":"Biophysical J."},{"key":"B16","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1016\/j.bbrc.2021.03.010","article-title":"C-terminal Troponin-I Residues Trap Tropomyosin in the Muscle Thin Filament Blocked-State","volume":"551","author":"Lehman","year":"2021","journal-title":"Biochem. Biophysical Res. Commun."},{"key":"B17","doi-asserted-by":"publisher","first-page":"1043","DOI":"10.1002\/cphy.c150030","article-title":"Thin Filament Structure and the Steric Blocking Model","volume":"6","author":"Lehman","year":"2016","journal-title":"Compr. Physiol."},{"key":"B18","doi-asserted-by":"publisher","first-page":"327","DOI":"10.1016\/j.jmb.2009.10.060","article-title":"The Shape and Flexibility of Tropomyosin Coiled Coils: Implications for Actin Filament Assembly and Regulation","volume":"395","author":"Li","year":"2010","journal-title":"J. Mol. Biol."},{"key":"B19","doi-asserted-by":"publisher","first-page":"1005","DOI":"10.1016\/j.bpj.2010.12.3697","article-title":"Tropomyosin Position on F-Actin Revealed by EM Reconstruction and Computational Chemistry","volume":"100","author":"Li","year":"2011","journal-title":"Biophysical J."},{"key":"B20","doi-asserted-by":"publisher","first-page":"108","DOI":"10.1006\/jmbi.1994.0070","article-title":"An Atomic Model of the Unregulated Thin Filament Obtained by X-Ray Fiber Diffraction on Oriented Actin-Tropomyosin Gels","volume":"246","author":"Lorenz","year":"1995","journal-title":"J. Mol. Biol."},{"key":"B21","doi-asserted-by":"publisher","first-page":"7405","DOI":"10.1021\/bi200506k","article-title":"A Model of Calcium Activation of the Cardiac Thin Filament","volume":"50","author":"Manning","year":"2011","journal-title":"Biochemistry"},{"key":"B22","doi-asserted-by":"publisher","first-page":"693","DOI":"10.1016\/s0006-3495(93)81110-x","article-title":"Regulation of the Interaction between Actin and Myosin Subfragment 1: Evidence for Three States of the Thin Filament","volume":"65","author":"McKillop","year":"1993","journal-title":"Biophysical J."},{"key":"B23","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1093\/cvr\/cvt071","article-title":"Familial Dilated Cardiomyopathy Mutations Uncouple Troponin I Phosphorylation from Changes in Myofibrillar Ca2+ Sensitivity","volume":"99","author":"Memo","year":"2013","journal-title":"Cardiovasc Res."},{"key":"B24","doi-asserted-by":"publisher","first-page":"7200","DOI":"10.1073\/pnas.0801950105","article-title":"Structural Basis for Tropomyosin Overlap in Thin (Actin) Filaments and the Generation of a Molecular Swivel by Troponin-T","volume":"105","author":"Murakami","year":"2008","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"B25","doi-asserted-by":"publisher","first-page":"694","DOI":"10.1016\/j.bpj.2014.06.034","article-title":"An Atomic Model of the Tropomyosin Cable on F-Actin","volume":"107","author":"Orzechowski","year":"2014","journal-title":"Biophysical J."},{"key":"B26","doi-asserted-by":"publisher","first-page":"2827","DOI":"10.1016\/s0006-3495(01)75924-3","article-title":"Disease-causing Mutations in Cardiac Troponin T: Identification of a Critical Tropomyosin-Binding Region","volume":"81","author":"Palm","year":"2001","journal-title":"Biophysical J."},{"key":"B27","doi-asserted-by":"publisher","first-page":"325","DOI":"10.1016\/j.bpj.2019.11.3393","article-title":"Docking Troponin T onto the Tropomyosin Overlapping Domain of Thin Filaments","volume":"118","author":"Pavadai","year":"2019","journal-title":"Biophys. J."},{"key":"B28","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1016\/j.bpj.2020.05.017","article-title":"Protein-Protein Docking Reveals Dynamic Interactions of Tropomyosin on Actin Filaments","volume":"119","author":"Pavadai","year":"2020","journal-title":"Biophysical J."},{"key":"B29","doi-asserted-by":"publisher","first-page":"109282","DOI":"10.1016\/j.abb.2022.109282","article-title":"Modulation of Cardiac Thin Filament Structure by Phosphorylated Troponin-I Analyzed by Protein-Protein Docking and Molecular Dynamics Simulation","volume":"725","author":"Pavadai","year":"2022","journal-title":"Archives Biochem. Biophysics"},{"key":"B30","doi-asserted-by":"publisher","first-page":"1605","DOI":"10.1002\/jcc.20084","article-title":"UCSF Chimera?A Visualization System for Exploratory Research and Analysis","volume":"25","author":"Pettersen","year":"2004","journal-title":"J. Comput. Chem."},{"key":"B31","doi-asserted-by":"publisher","first-page":"17128","DOI":"10.1074\/jbc.ra120.014713","article-title":"M8R Tropomyosin Mutation Disrupts Actin Binding and Filament Regulation: The Beginning Affects the Middle and End","volume":"295","author":"Racca","year":"2020","journal-title":"J. Biol. Chem."},{"key":"B32","doi-asserted-by":"publisher","first-page":"e2024288118","DOI":"10.1073\/pnas.2024288118","article-title":"The Structure of the Native Cardiac Thin Filament at Systolic Ca2+ Levels","volume":"118","author":"Risi","year":"","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B33","doi-asserted-by":"publisher","first-page":"50","DOI":"10.1016\/j.str.2020.09.013","article-title":"High-Resolution Cryo-EM Structure of the Cardiac Actomyosin Complex","volume":"29","author":"Risi","year":"","journal-title":"Structure"},{"key":"B34","doi-asserted-by":"publisher","first-page":"525","DOI":"10.1007\/s10974-015-9419-z","article-title":"Electrostatic Interaction Map Reveals a New Binding Position for Tropomyosin on F-Actin","volume":"36","author":"Rynkiewicz","year":"2015","journal-title":"J. Muscle Res. Cell Motil."},{"key":"B35","doi-asserted-by":"publisher","first-page":"e202012640","DOI":"10.1085\/jgp.202012640","article-title":"Loss of Crossbridge Inhibition Drives Pathological Cardiac Hypertrophy in Patients Harboring the TPM1 E192K Mutation","volume":"153","author":"Sewanan","year":"2021","journal-title":"J. Gen. Physiol."},{"key":"B36","doi-asserted-by":"publisher","first-page":"54","DOI":"10.1006\/jsbi.2002.4454","article-title":"Analysis of \u03b1-Helical Coiled Coils with the Program TWISTER Reveals a Structural Mechanism for Stutter Compensation","volume":"137","author":"Strelkov","year":"2002","journal-title":"J. Struct. Biol."},{"key":"B37","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1038\/nature01780","article-title":"Structure of the Core Domain of Human Cardiac Troponin in the Ca2+-Saturated Form","volume":"424","author":"Takeda","year":"2003","journal-title":"Nature"},{"key":"B38","doi-asserted-by":"publisher","first-page":"27636","DOI":"10.1074\/jbc.m201768200","article-title":"The Troponin Tail Domain Promotes a Conformational State of the Thin Filament that Suppresses Myosin Activity","volume":"277","author":"Tobacman","year":"2002","journal-title":"J. Biol. Chem."},{"key":"B39","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.bpj.2020.11.014","article-title":"Troponin Revealed: Uncovering the Structure of the Thin Filament On-Off Switch in Striated Muscle","volume":"120","author":"Tobacman","year":"2021","journal-title":"Biophysical J."},{"key":"B40","doi-asserted-by":"publisher","first-page":"673","DOI":"10.1016\/j.str.2008.03.005","article-title":"Flexible Fitting of Atomic Structures into Electron Microscopy Maps Using Molecular Dynamics","volume":"16","author":"Trabuco","year":"2008","journal-title":"Structure"},{"key":"B41","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1006\/jmbi.1996.0800","article-title":"Steric-model for Activation of Muscle Thin Filaments","volume":"266","author":"Vibert","year":"1997","journal-title":"J. Mol. Biol."},{"key":"B42","doi-asserted-by":"publisher","first-page":"eabn1934","DOI":"10.1126\/science.abn1934","article-title":"Structures from Intact Myofibrils Reveal Mechanism of Thin Filament Regulation through Nebulin","volume":"375","author":"Wang","year":"2022","journal-title":"Science"},{"key":"B43","doi-asserted-by":"publisher","first-page":"2135","DOI":"10.1016\/j.cell.2021.02.047","article-title":"The Molecular Basis for Sarcomere Organization in Vertebrate Skeletal Muscle","volume":"184","author":"Wang","year":"2021","journal-title":"Cell"},{"key":"B44","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1002\/(sici)1097-0134(20000101)38:1<49:aid-prot6>3.0.co;2-b","article-title":"Crystal Structure of Tropomyosin at 7 \u00c5ngstroms Resolution","volume":"38","author":"Whitby","year":"2000","journal-title":"Proteins"},{"key":"B45","doi-asserted-by":"publisher","first-page":"3301","DOI":"10.1021\/acs.jpclett.8b00958","article-title":"Mechanism of Cardiac Tropomyosin Transitions on Filamentous Actin as Revealed by All-Atom Steered Molecular Dynamics Simulations","volume":"9","author":"Williams","year":"2018","journal-title":"J. Phys. Chem. Lett."},{"key":"B46","doi-asserted-by":"publisher","first-page":"153","DOI":"10.1038\/s41467-019-14008-1","article-title":"Cardiac Muscle Thin Filament Structures Reveal Calcium Regulatory Mechanism","volume":"11","author":"Yamada","year":"2020","journal-title":"Nat. Commun."}],"container-title":["Frontiers in Physiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphys.2022.932333\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,6,22]],"date-time":"2022-06-22T06:44:04Z","timestamp":1655880244000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphys.2022.932333\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,6,22]]},"references-count":46,"alternative-id":["10.3389\/fphys.2022.932333"],"URL":"https:\/\/doi.org\/10.3389\/fphys.2022.932333","relation":{},"ISSN":["1664-042X"],"issn-type":[{"value":"1664-042X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,6,22]]},"article-number":"932333"}}