Article
Biochemistry & Molecular Biology
Priyanka Parijat, Laszlo Kondacs, Alexander Alexandrovich, Mathias Gautel, Alexander J. A. Cobb, Thomas Kampourakis
Summary: Current therapeutic interventions for heart disease and heart failure are insufficient and associated with side effects. Research targeting sarcomeric proteins and identifying small molecule effectors for cardiac thin filament activation pathway have shown potential, with fingolimod identified as a new lead compound for heart failure therapeutics.
ACS CHEMICAL BIOLOGY
(2021)
Article
Biophysics
Anja M. Touma, Wanjian Tang, David Rasicci, Duha Vang, Ashim Rai, Samantha B. Previs, David M. Warshaw, Christopher M. Yengo, Sivaraj Sivaramakrishnan
Summary: The nanosurfer assay provides a platform for precise manipulation of spatially dependent cMyBP-C binding-partner interactions, shedding light on the molecular regulation of beta-cardiac myosin contractility.
BIOPHYSICAL JOURNAL
(2022)
Article
Chemistry, Medicinal
Eric R. Hantz, Steffen Lindert
Summary: This study computationally characterized the effects of eight mutations in cNTnC on calcium binding affinity. The results showed a trend of increased calcium sensitivity for all mutations, with five mutants predicted to increase sensitivity in site II. This comparison of two computational methods provides valuable insights into the impacts of calcium sensitivity in mutant cNTnC systems.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2022)
Review
Physiology
Christopher Sol, R. John Solaro
Summary: This review focuses on sarcomere regulatory mechanisms, specifically discussing cardiac-specific modifications to the three-state model of thin filament activation. It highlights the modulation of thin filament transitions by Ca2+, crossbridge interactions, and thick filament-associated proteins. The role of cMyBP-C, cRLC, and titin filaments in these processes is crucial for understanding physiological cardiac states and developing therapies for cardiac disorders.
JOURNAL OF GENERAL PHYSIOLOGY
(2021)
Article
Medicine, Research & Experimental
Martijn van de Locht, Sandra Donkervoort, Josine M. de Winter, Stefan Conijn, Leon Begthel, Benno Kusters, Payam Mohassel, Ying Hu, Livija Medne, Colin Quinn, Steven A. Moore, A. Reghan Foley, Gwimoon Seo, Darren T. Hwee, Fady Malik, Thomas Irving, Weikang Ma, Henk L. Granzier, Erik-Jan Kamsteeg, Kalyan Immadisetty, Peter Kekenes-Huskey, Jose R. Pinto, Nicol Voermans, Carsten G. Bonnemann, Coen A. C. Ottenheijm
Summary: Pathogenic variants in TNNC2 have been identified to cause congenital muscle disease, leading to disruptions in Ca2+ binding sites and troponin I binding sites which result in reduced force response of sarcomeres. By replacing mutant TnC with wild-type TnC or using the troponin activator tirasemtiv, contractile dysfunction in patients' myofibers can be repaired, providing therapeutic potential for muscle contractility.
JOURNAL OF CLINICAL INVESTIGATION
(2021)
Article
Multidisciplinary Sciences
Dian Ding, Tianyi Hou, Miao Wei, Jing-Xiang Wu, Lei Chen
Summary: Cardiac KATP channels containing SUR2A have a different sensitivity to Mg-ADP activation compared to other subtypes. This study reveals a regulatory helix that inhibits SUR2A activation and provides cryo-EM structures of SUR2A and SUR2B to investigate the underlying mechanism. The findings suggest that the R helix stabilizes SUR2A in an inhibited conformation and the binding of Mg-ADP relieves this inhibition, allowing channel activation.
NATURE COMMUNICATIONS
(2023)
Article
Biology
Luca Livraghi, Joseph J. Hanly, Steven M. Van Bellghem, Gabriela Montejo-Kovacevich, Eva S. M. van Der Heijden, Ling Sheng Loh, Anna Ren, Ian A. Warren, James J. Lewis, Carolina Concha, Laura Hebberecht, Charlotte J. Wright, Jonah M. Walker, Jessica Foley, Zachary H. Goldberg, Henry Arenas-Castro, Camilo Salazar, Michael W. Perry, Riccardo Papa, Arnaud Martin, W. Owen McMillan, Chris D. Jiggins
Summary: In Heliconius butterflies, wing color pattern diversity and scale types are controlled by a few genes of large effect, which regulate color pattern switches between morphs and species. The gene cortex is identified as a major determinant of scale cell identity through CRISPR knockouts in multiple Heliconius species. Chromatin accessibility profiling and introgression scans reveal cis-regulatory regions associated with discrete phenotypic switches.
Article
Biochemistry & Molecular Biology
Carlos Henrique Vieira-Vieira, Vita Dauksaite, Anje Sporbert, Michael Gotthardt, Matthias Selbach
Summary: Researchers have developed a quantitative RNA-interactome capture method to assess the function of phosphorylation sites in RNA-binding proteins.
Article
Biochemistry & Molecular Biology
Georgi Z. Genchev, Minae Kobayashi, Tomoyoshi Kobayashi, Hui Lu
Summary: Understanding the molecular regulation of cardiac muscle contraction is essential for developing therapies for heart conditions. This study explored the equilibrium dynamics of cardiac muscle protein troponin and highlighted key interactions between TnC and TnI that could potentially modulate cardiac contractility, offering new therapeutic targets.
Article
Chemistry, Medicinal
Eric R. Hantz, Steffen Lindert
Summary: This study utilized adaptive steered molecular dynamics to investigate the impact of N-cTnC mutations on site II calcium binding affinity, demonstrating correct trends for various mutants and showing increased potential of mean force accuracy with slower speeds and fewer trajectories. This novel approach provides a valuable tool for estimating calcium binding affinity of N-cTnC structures and supporting the design of potentially therapeutic mutations.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2021)
Article
Cardiac & Cardiovascular Systems
Jenette G. Creso, Stuart G. Campbell
Summary: It has been found that assuming TnI regulates Tm movement via two actin-binding domains rather than one can achieve the same degree of Ca2+ regulation with lower affinity for actin. Experimental data shows that disruption of either the IP or MD leads to qualitative changes in several properties. Simulations suggest that both domains are needed to minimize diastolic cross-bridge activity and accelerate myofilament relaxation.
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
(2021)
Article
Multidisciplinary Sciences
Maicon Landim-Vieira, Weikang Ma, Taejeong Song, Hosna Rastegarpouyani, Henry Gong, Isabella Leite Coscarella, Sylvia J. P. Bogaards, Stefan P. Conijn, Coen A. C. Ottenheijm, Hyun S. Hwang, Maria Papadaki, Bjorn C. Knollmann, Sakthivel Sadayappan, Thomas C. Irving, Vitold E. Galkin, P. Bryant Chase, Jose Renato Pinto
Summary: Missense variant Ile79Asn in human cardiac troponin T (cTnT-I79N) is associated with hypertrophic cardiomyopathy and sudden cardiac arrest. A recent study showed that cTnT-I79N destabilizes the relaxed state of the cardiac thin filament, resulting in increased myofilament Ca2+ sensitivity and slower crossbridge kinetics. This is likely due to the weakening of the interaction between the TnT1 loop and actin filament.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2023)
Article
Chemistry, Physical
D'Artagnan Greene, Michael Barton, Tyler Luchko, Yohannes Shiferaw
Summary: This study investigates the gating mechanism of the cardiac ryanodine receptor type 2 (RyR2) using molecular dynamics simulations. The position of the S4-S5 linker on a single subunit is found to determine the overall open or closed state of the channel. In addition, high percent occupancy interactions between adjacent subunits are crucial for channel gating. Analysis of CPVT1 mutations reveals that disruption of these cooperative interactions is a primary cause of channel leak and CPVT.
JOURNAL OF PHYSICAL CHEMISTRY B
(2022)
Article
Medicine, Research & Experimental
Allison B. Mason, Melissa L. Lynn, Anthony P. Baldo, Andrea E. Deranek, Jil C. Tardiff, Steven D. Schwartz
Summary: This study utilized computational modeling to predict and simulate the effects of mutations on cardiac thin filament proteins. Experimental validation was used to identify pathogenic signatures and reclassify variants, providing unique structural and dynamic information for classification of both new and conflicting variants.
Article
Immunology
Fangwei Leng, Wenxiang Zhang, Ricardo N. Ramirez, Juliette Leon, Yi Zhong, Lifei Hou, Koichi Yuki, Joris van der Veeken, Alexander Y. Rudensky, Christophe Benoist, Sun Hur
Summary: It has been discovered that FoxP3 can exist in two different dimerization forms, head-to-head dimerization and swap dimerization, with the former being associated with functional specificity and the latter being associated with functional impairment.
Article
Multidisciplinary Sciences
Varnavas D. Mouchlis, Daiki Hayashi, Alexis M. Vasquez, Jian Cao, J. Andrew McCammon, Edward A. Dennis
Summary: Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) associates with lipoproteins in human plasma and hydrolyzes oxidized phospholipids. The mechanism of enzyme-membrane association and substrate specificity were studied using lipidomics and mass spectrometry techniques.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Multidisciplinary Sciences
Thomas G. Laughlin, Amar Deep, Amy M. Prichard, Christian Seitz, Yajie Gu, Eray Enustun, Sergey Suslov, Kanika Khanna, Erica A. Birkholz, Emily Armbruster, J. Andrew McCammon, Rommie E. Amaro, Joe Pogliano, Kevin D. Corbett, Elizabeth Villa
Summary: This study identifies a protein called ChmA as the main component of the bacteriophage nuclear shell. The structure and dynamics of the ChmA shell provide insights into its formation and functions.
Article
Biochemistry & Molecular Biology
Surl-Hee Ahn, Gary A. Huber, J. Andrew McCammon
Summary: Intrinsically disordered proteins (IDPs) have attracted significant attention due to their involvement in biological processes and diseases. Computational studies using Brownian dynamics (BD) simulations with a coarse-grained force field for proteins (COFFDROP) have been conducted to complement experimental work. The researchers found that IDPs' properties, such as hydrodynamic radii and entanglement indices, are influenced by salt concentration.
FRONTIERS IN MOLECULAR BIOSCIENCES
(2022)
Article
Biochemistry & Molecular Biology
Joshua C. Corpuz, Ashay Patel, Tony D. Davis, Larissa M. Podust, J. Andrew McCammon, Michael D. Burkart
Summary: This study reveals the binding specificities between peptidyl carrier proteins (PCPs) and adenylation (A) domains in non-ribosomal peptide synthetases (NRPSs) using chemical biology approaches. The research also demonstrates the possibility of controlling PCP binding specificity through modifying interfacial interactions.
ACS CHEMICAL BIOLOGY
(2022)
Article
Chemistry, Medicinal
Eric R. Hantz, Steffen Lindert
Summary: This study computationally characterized the effects of eight mutations in cNTnC on calcium binding affinity. The results showed a trend of increased calcium sensitivity for all mutations, with five mutants predicted to increase sensitivity in site II. This comparison of two computational methods provides valuable insights into the impacts of calcium sensitivity in mutant cNTnC systems.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2022)
Article
Multidisciplinary Sciences
Zachary C. Drake, Justin T. Seffernick, Steffen Lindert
Summary: Covalent labeling (CL) in combination with mass spectrometry is a useful tool for studying and determining structural properties of protein-protein complexes. However, the data from these experiments is limited and does not provide a clear understanding of protein structure. This study presents a hybrid method that combines models of protein complex subunits generated with AlphaFold and differential CL data through a CL-guided protein-protein docking in Rosetta. The results show that this integrated approach can effectively utilize CL data to distinguish between nativelike and non-nativelike models.
NATURE COMMUNICATIONS
(2022)
Article
Multidisciplinary Sciences
Yohei Takahashi, Krystal C. Bosmans, Po -Kai Hsu, Karnelia Paul, Christian Seitz, Chung-Yueh Yeh, Yuh-Shuh Wang, Dmitry Yarmolinsky, Maija Sierla, Triin Vahisalu, J. Andrew McCammon, Jaakko Kangasjaervi, Li Zhang, Hannes Kollist, Thien Trac, Julian I. Schroeder
Summary: The rise in atmospheric CO2 concentration affects stomatal closing in plants, impacting transpirational water loss, photosynthesis, and growth. This study identifies MPK4/12 and HT1 as the primary CO2 sensors in plants, located upstream of the CBC1 kinase. These findings are significant for understanding the plant response to CO2.
Article
Biochemistry & Molecular Biology
Jui-Hung Weng, Wen Ma, Jian Wu, Pallavi Kaila Sharma, Steve Silletti, J. Andrew McCammon, Susan Taylor
Summary: Mutations in LRRK2 increase the risk of Parkinson's disease, and its pathological functions are often associated with abnormal kinase activity. This study combines enhanced sampling simulations with HDX-MS to investigate the dynamic changes and allosteric communications within the C-terminal domains of LRRK2. It is found that different types of kinase inhibitors stabilize distinct kinase conformations and modulate the interdomain interactions between the kinase and GTPase domains.
ACS CHEMICAL BIOLOGY
(2023)
Article
Chemistry, Medicinal
Eric R. R. Hantz, Svetlana B. B. Tikunova, Natalya Belevych, Jonathan P. P. Davis, Peter J. J. Reiser, Steffen Lindert
Summary: Despite significant investments, heart failure caused by contractile apparatus disruption remains a major cause of death. This study focused on finding small molecules that can enhance calcium sensitivity without impacting calcium concentration, thus improving cardiac function. The researchers used various muscle systems to examine the effect of a calcium-sensitizing compound and identified three novel low-affinity binders with similar affinities to a known positive inotrope. The most potent calcium sensitizer identified was compound 16 with an apparent affinity of 117 ± 17 μM.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2023)
Article
Chemistry, Medicinal
Austin M. Cool, Steffen Lindert
Summary: The cardiac thin filament, consisting of F-actin, tropomyosin, and troponin(cTn), plays a crucial role in cardiac muscle function. Investigating the effect of the thin filament on cTn activation events, computational simulations revealed that it causes changes in free energy and interaction between different subunits of cTn. Mutations in the cTn complex can lead to heart diseases like cardiomyopathy, impairing cardiac muscle function. By using a more physiologically relevant thin-filament model, the study observed the consequences of cardiomyopathic mutations on cTn complex that would be impossible with isolated computational studies, highlighting the importance of a comprehensive approach.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2023)
Article
Biochemistry & Molecular Biology
Sravya Kovvali, Yuan Gao, Austin Cool, Steffen Lindert, Vicki H. Wysocki, Charles E. Bell, Venkat Gopalan
Summary: Amadori rearrangement products are stable sugar-amino acid conjugates that are formed nonenzymatically during food processing. Understanding bacterial utilization of these fructosamines is crucial due to their impact on the animal gut microbiome. In this study, the catalytic mechanism of the deglycase enzyme FrlB was elucidated through crystallography, computational docking, biochemical assays, and native mass spectrometry. The findings provide insights into the structure-function relationship and mechanisms of enzymes.
Article
Biochemistry & Molecular Biology
Terra Sztain, Joshua C. Corpuz, Thomas G. Bartholow, Javier O. Sanlley Hernandez, Ziran Jiang, Desirae A. Mellor, Graham W. Heberlig, James J. La Clair, J. Andrew Mccammon, Michael D. Burkart
Summary: Carrier-protein-dependent metabolic pathways rely on protein-protein interactions to control enzyme reactivity and timing. Computational methods, such as the improved Rosetta score function, can be used to design customized pathways by optimizing protein-protein interactions. This method provides a promising platform for engineering carrier-protein-dependent pathways.
ACS CHEMICAL BIOLOGY
(2023)
Article
Biochemical Research Methods
S. M. Bargeen Alam Turzo, Justin T. Seffernick, Sergey Lyskov, Steffen Lindert
Summary: This article introduces a method for predicting collision cross section (CCSIM) based on protein structures using the projection approximation with PARCS on the Rosetta Online Server that Includes Everyone (ROSIE) webserver. The user only needs to provide one or more PDB files as input. Results show that CCSIM predictions with ROSIE-PARCS are highly accurate, with an average error of 6.12%. Furthermore, the absolute difference between CCSIM and CCSPARCS can help distinguish accurate and inaccurate AlphaFold2 protein structure predictions.
BRIEFINGS IN BIOINFORMATICS
(2023)
Article
Physics, Applied
Marcus T. Hock, Abigail E. Teitgen, Kimberly J. McCabe, Sophia P. Hirakis, Gary A. Huber, Michael Regnier, Rommie E. Amaro, J. Andrew McCammon, Andrew D. McCulloch
Summary: dATP, a natural analog of ATP, has been shown to enhance cardiac function. In this study, computational modeling was used to investigate the mechanism by which dATP accelerates calcium re-uptake into the sarcoplasmic reticulum during cardiac relaxation. The results showed that dATP interacts with SERCA and increases calcium association rate constants, ultimately leading to accelerated calcium transient decay observed experimentally.
JOURNAL OF APPLIED PHYSICS
(2023)
Article
Chemistry, Physical
Christian Seitz, Ilker Deveci, J. Andrew McCammon
Summary: This study investigates how protein glycosylation and lateral crowding effects modulate the stability and dynamics of influenza neuraminidase. The results show that glycans stabilize the protein structure, while a crowded membrane environment encourages large-scale conformational changes.
JOURNAL OF PHYSICAL CHEMISTRY LETTERS
(2023)