ArticleThe journal of physical chemistry. B2018
Molecular Dynamics and Umbrella Sampling Simulations Elucidate Differences in Troponin C Isoform and Mutant Hydrophobic Patch Exposure.
Article in The journal of physical chemistry. B, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 30 citations in OpenAlex.
- Computational studies on the catalytic potential of the double active site for enzyme engineering.Scientific reports · 2024Article
- Article
- Umbrella Sampling Simulations of Cardiac Thin Filament Reveal Thermodynamic Consequences of Troponin I Inhibitory Peptide Mutations.Journal of chemical information and modeling · 2023Article
- 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
- Computational Exploration and Characterization of Potential Calcium Sensitizing Mutations in Cardiac Troponin C.Journal of chemical information and modeling · 2022Article
- The effect of MgThe FEBS journal · 2022Article
- Umbrella Sampling Simulations Measure Switch Peptide Binding and Hydrophobic Patch Opening Free Energies in Cardiac Troponin.Journal of chemical information and modeling · 2022Article
- Free-Energy Surfaces of Two Cardiac Thin Filament Conformational Changes during Muscle Contraction.The journal of physical chemistry. B · 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
- Multiscale Models of Cardiac Muscle Biophysics and Tissue Remodeling in Hypertrophic Cardiomyopathies.Current opinion in biomedical engineering · 2019Article
- Mechanism of Cardiac Troponin C Calcium Sensitivity Modulation by Small Molecules Illuminated by Umbrella Sampling Simulations.Journal of chemical information and modeling · 2019Article
- In vitro analyses of suspected arrhythmogenic thin filament variants as a cause of sudden cardiac death in infants.Proceedings of the National Academy of Sciences of the United States of America · 2019Article
- Article
- Computational Studies of Cardiac and Skeletal Troponin.Frontiers in molecular biosciences · 2019Review
- Binding of calcium and magnesium to human cardiac troponin C.The Journal of biological chemistryArticle
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
Abstract
Troponin C (TnC) facilitates muscle contraction through calcium-binding within its N-terminal region (NTnC). As previously observed using molecular dynamics (MD) simulations, this calcium-binding event leads to an increase in the dynamics of helices lining a hydrophobic patch on TnC. Simulation times of multiple microseconds were required to even see a partial opening of the hydrophobic patch, limiting the ability to thoroughly and quantitatively investigate these rare events. Here we describe the application of umbrella sampling to probe the TnC hydrophobic patch opening in a more targeted and quantitative fashion. Umbrella sampling was utilized to investigate the differences in the free energy of opening between cardiac (cTnC) and fast skeletal TnC (sTnC). We found that, in agreement with previous reports, holo (calcium-bound) sTnC had a lower free energy of opening compared with holo cTnC. Additionally, differences in the free energy of opening of hypertrophic (HCM) and dilated cardiomyopathy (DCM) cTnC systems were investigated. MD simulations and umbrella sampling revealed a lower free energy of opening for the HCM mutations A8V and A31S, as well as the calcium-sensitizing mutation L48Q. The DCM mutations, Y5H, Q50R, and E59D/D75Y, all exhibited a higher free energy of opening. An umbrella sampling simulation of cTnI-bound holo cTnC exhibited the lowest free energy in the open configuration, in agreement with experimental data. In conclusion, this study presents a novel and successful protocol for applying umbrella sampling simulations to quantitatively study the molecular basis of muscle contraction and proposes a mechanism by which HCM and DCM-associated mutations influence contraction.
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