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Conformational Analysis of Heparin-Analogue Pentasaccharides by Nuclear Magnetic Resonance Spectroscopy and Molecular Dynamics Simulations

  • Gábor Balogh
    Gábor Balogh
    Division of Clinical Laboratory Science, Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, Nagyerdei krt. 98, H-4032 Debrecen, Hungary
  • Tamás Gyöngyösi
    Tamás Gyöngyösi
    Department of Inorganic and Analytical Chemistry, University of Debrecen, Egyetem tér 1, H-4032 Debrecen, Hungary
    MTA−DE Molecular Recognition and Interaction Research Group, University of Debrecen, Egyetem tér 1, H-4032 Debrecen, Hungary
  • István Timári
    István Timári
    Department of Inorganic and Analytical Chemistry, University of Debrecen, Egyetem tér 1, H-4032 Debrecen, Hungary
  • Mihály Herczeg
    Mihály Herczeg
    Department of Pharmaceutical Chemistry, University of Debrecen, Egyetem tér 1, H-4032 Debrecen, Hungary
    Research Group for Oligosaccharide Chemistry of Hungarian Academy of Sciences, University of Debrecen, Egyetem tér 1, H-4032 Debrecen, Hungary
  • Anikó Borbás
    Anikó Borbás
    Department of Pharmaceutical Chemistry, University of Debrecen, Egyetem tér 1, H-4032 Debrecen, Hungary
  • S. Kashif Sadiq*
    S. Kashif Sadiq
    Heidelberg Institute for Theoretical Studies, Schloss-Wolfsbrunnenweg 35, 69118 Heidelberg, Germany
    European Molecular Biology Laboratory, Meyerhofstrasse 1, 69117 Heidelberg, Germany
    *Email: [email protected]
  • Krisztina Fehér*
    Krisztina Fehér
    MTA−DE Molecular Recognition and Interaction Research Group, University of Debrecen, Egyetem tér 1, H-4032 Debrecen, Hungary
    *Email: [email protected]
  • , and 
  • Katalin E. Kövér*
    Katalin E. Kövér
    Department of Inorganic and Analytical Chemistry, University of Debrecen, Egyetem tér 1, H-4032 Debrecen, Hungary
    MTA−DE Molecular Recognition and Interaction Research Group, University of Debrecen, Egyetem tér 1, H-4032 Debrecen, Hungary
    *Email: [email protected]
Cite this: J. Chem. Inf. Model. 2021, 61, 6, 2926–2936
Publication Date (Web):May 24, 2021
https://doi.org/10.1021/acs.jcim.1c00200
Copyright © 2021 American Chemical Society

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    Abstract

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    Elucidation and improvement of the blood coagulant properties of heparin are the focus of intense research. In this study, we performed conformational analysis using nuclear magnetic resonance (NMR) spectroscopy and molecular dynamics (MD) simulations on the heparin pentasaccharide analogue idraparinux, its disulfonatomethyl analogue, which features a slightly improved blood coagulation property, and a trisulfonatomethyl analogue, in which the activity has been totally abolished. As the ring conformation of the G subunit has been suggested as a major determinant of the biological properties, we analyzed the sugar ring conformations and dynamics of the interglycosidic linkages. We found that the conformation of the G ring is dominated by the 2SO skewed boat next to the 1C4 chair in all three derivatives. Both the thermodynamics and the kinetics of the conformational states were found to be highly similar in the three derivatives. Molecular kinetic analysis showed that the 2SO skewed boat state of the G ring is equally favorable in the three analogues, resulting in similar 2SO populations. Also, the transition kinetics from the 1C4 chair to the 2SO skewed boat was found to be comparable in the derivatives, which indicates a similar energy barrier between the two states of the G subunit. We also identified a slower conformational transition between the dominant 4C1 chair and the boat conformations on the E subunit. Both G and E ring flips are also accompanied by changes along the interglycosidic linkages, which take place highly synchronously with the ring flips. These findings indicate that conformational plasticity of the G ring and the dominance of the 2SO skewed boat populations do not necessarily warrant the biological activity of the derivatives and hence the impact of other factors also needs to be considered.

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    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.jcim.1c00200.

    • Experimental homonuclear vicinal coupling constants in the different rings determined for the derivatives 1, 2, and 3 (Table S1); comparison of the distances from equilibrium MD corresponding to nuclear overhauser effects (NOE) between 1H nuclei (Table S2); time evolution of the Cremer–Pople θ and φ parameters and that of interglycosidic φ (in red) and ψ (in blue) torsion angles during the 10 replica equilibrium MD simulations for the different subunits for derivatives 1 in (a), for 2 in (b) and for 3 in (c) (Figure S1); calculated RMSD values of the conformations in the trajectories using bound pentasaccharide in 1E03 as a reference (Figure S2) (PDF)

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    Cited By

    This article is cited by 7 publications.

    1. Mihály Herczeg, Fruzsina Demeter, Erika Lisztes, Márk Racskó, Balázs István Tóth, István Timári, Zsuzsanna Bereczky, Katalin E. Kövér, Anikó Borbás. Synthesis of a Heparinoid Pentasaccharide Containing l-Guluronic Acid Instead of l-Iduronic Acid with Preserved Anticoagulant Activity. The Journal of Organic Chemistry 2022, 87 (23) , 15830-15836. https://doi.org/10.1021/acs.joc.2c01928
    2. Serge Perez, Olga Makshakova. Multifaceted Computational Modeling in Glycoscience. Chemical Reviews 2022, 122 (20) , 15914-15970. https://doi.org/10.1021/acs.chemrev.2c00060
    3. Rajarshi Roy, Nisha Amarnath Jonniya, Parimal Kar. Effect of Sulfation on the Conformational Dynamics of Dermatan Sulfate Glycosaminoglycan: A Gaussian Accelerated Molecular Dynamics Study. The Journal of Physical Chemistry B 2022, 126 (21) , 3852-3866. https://doi.org/10.1021/acs.jpcb.2c01807
    4. J. Joel Janke, Yanlei Yu, Vitor H. Pomin, Jing Zhao, Chunyu Wang, Robert J. Linhardt, Angel E. García. Characterization of Heparin’s Conformational Ensemble by Molecular Dynamics Simulations and Nuclear Magnetic Resonance Spectroscopy. Journal of Chemical Theory and Computation 2022, 18 (3) , 1894-1904. https://doi.org/10.1021/acs.jctc.1c00760
    5. Balaji Nagarajan, Samuel G. Holmes, Nehru Viji Sankaranarayanan, Umesh R. Desai. Molecular dynamics simulations to understand glycosaminoglycan interactions in the free- and protein-bound states. Current Opinion in Structural Biology 2022, 74 , 102356. https://doi.org/10.1016/j.sbi.2022.102356
    6. Cuiping Huang, Jian Cao, Mingming Liu, Yajing Tu, Meijuan Zhang, Junying Zheng. A Turn‐On Sensor for Highly Sensitive and Selective Detect Heparin in Human Serum Albumin. ChemistrySelect 2022, 7 (15) https://doi.org/10.1002/slct.202200363
    7. Mária Raics, Álex Kálmán Balogh, Chandan Kishor, István Timári, Francisco J. Medrano, Antonio Romero, Rob Marc Go, Helen Blanchard, László Szilágyi, Katalin E. Kövér, Krisztina Fehér. Investigation of the Molecular Details of the Interactions of Selenoglycosides and Human Galectin-3. International Journal of Molecular Sciences 2022, 23 (5) , 2494. https://doi.org/10.3390/ijms23052494

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