ArticleJournal of chemical information and modeling2019
Mechanism of Cardiac Troponin C Calcium Sensitivity Modulation by Small Molecules Illuminated by Umbrella Sampling Simulations.
Article in Journal of chemical information and modeling, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
12 citing papers in PubMed, 13 citations in OpenAlex.
- Transcriptome and DNA Methylation Analyses Provide Insight into Environmental Adaptation in Northern and Southern Populations ofAnimals : an open access journal from MDPI · 2026Article
- Omecamtiv Mecarbil in the treatment of heart failure: the past, the present, and the future.Frontiers in cardiovascular medicine · 2024Review
- Targeting Troponin C with Small Molecules Containing Diphenyl Moieties: Calcium Sensitivity Effects on Striated Muscles and Structure-Activity Relationship.Journal of chemical information and modeling · 2023Article
- Targeting Troponin C with Small Molecules Containing Diphenyl Moieties: Calcium Sensitivity Effects on Striated Muscle and Structure Activity Relationship.bioRxiv : the preprint server for biology · 2023Article
- Methods for assessing cardiac myofilament calcium sensitivity.Frontiers in physiology · 2023Review
- Computational Exploration and Characterization of Potential Calcium Sensitizing Mutations in Cardiac Troponin C.Journal of chemical information and modeling · 2022Article
- Umbrella Sampling Simulations Measure Switch Peptide Binding and Hydrophobic Patch Opening Free Energies in Cardiac Troponin.Journal of chemical information and modeling · 2022Article
- Computational Methods Elucidate Consequences of Mutations and Post-translational Modifications on Troponin I Effective Concentration to Troponin C.The journal of physical chemistry. B · 2021Article
- Adaptative Steered Molecular Dynamics Study of Mutagenesis Effects on Calcium Affinity in the Regulatory Domain of Cardiac Troponin C.Journal of chemical information and modeling · 2021Article
- Discovery of Novel Small-Molecule Calcium Sensitizers for Cardiac Troponin C: A Combined Virtual and Experimental Screening Approach.Journal of chemical information and modeling · 2020Article
- Advances and Challenges in Rational Drug Design for SLCs.Trends in pharmacological sciences · 2019Review
- Computational Studies of Cardiac and Skeletal Troponin.Frontiers in molecular biosciences · 2019Review
Corrections and comments
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
Cardiac troponin C (cTnC) binds intracellular calcium and subsequently cardiac troponin I (cTnI), initiating cardiac muscle contraction. Due to its role in contraction, cTnC has been a therapeutic target in the search for small molecules to treat conditions that interfere with normal muscle contraction like the heritable cardiomyopathies. Structural studies have shown the binding location of small molecules such as bepridil, dfbp-o, 3-methyldiphenylamine (DPA), and W7 to be a hydrophobic pocket in the regulatory domain of cTnC (cNTnC) but have not shown the influence of these small molecules on the energetics of opening this domain. Here we describe an application of an umbrella sampling method used to elucidate the impact these calcium sensitivity modulators have on the free energy of cNTnC hydrophobic patch opening. We found that all these molecules lowered the free energy of opening in the absence of the cTnI, with bepridil facilitating the least endergonic transformation. In the presence of cTnI, however, we saw a stabilization of the open configuration due to DPA and dfbp-o binding, and a destabilization of the open configuration imparted by bepridil and W7. Predicted poor binding molecule NSC34337 left the hydrophobic patch in under 3 ns in conventional MD simulations suggesting that only hydrophobic patch binders stabilized the open conformation. In conclusion, this study presents a novel approach to study the impact of small molecules on hydrophobic patch opening through umbrella sampling, and it proposes mechanisms for calcium sensitivity modulation.
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