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The mechanism of high affinity pentasaccharide binding to antithrombin, insights from Gaussian accelerated molecular dynamics simulations.

Authors
  • Balogh, Gábor1, 2
  • Komáromi, István1
  • Bereczky, Zsuzsanna1
  • 1 Division of Clinical Laboratory Science, Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary. , (Hungary)
  • 2 Kálmán Laki Doctoral School, University of Debrecen, Debrecen, Hungary. , (Hungary)
Type
Published Article
Journal
Journal of biomolecular structure & dynamics
Publication Date
Oct 01, 2020
Volume
38
Issue
16
Pages
4718–4732
Identifiers
DOI: 10.1080/07391102.2019.1688194
PMID: 31686597
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

The activity of antithrombin (AT), a serpin protease inhibitor, is enhanced by heparin and heparin analogs against its target proteases, mainly thrombin, factors Xa and IXa. Considerable amount of information is available on the multistep mechanism of the heparin pentasaccharide binding and conformational activation. However, much of the details were inferred from 'static' structures obtained by X-ray diffraction. Moreover, limited information is available for the early steps of binding mechanism other than kinetic studies with various ligands. To gain insights into these processes, we performed enhanced sampling molecular dynamics (MD) simulations using the Gaussian Accelerated Molecular Dynamics (GAMD) method, applied previously in drug binding studies. We were able to observe the binding of the pentasaccharide idraparinux to a 'non-activated' AT conformation in two separate trajectories with low root mean square deviation (RMSD) values compared to X-ray structures of the bound state. These trajectories along with further simulations of the AT-pentasaccharide complex provided insights into the mechanisms of multiple conformational transitions, including the expulsion of the hinge region, the extension of helix D and the conformational behavior of the reactive center loop (RCL). We could also confirm the high stability of helix P in non-activated AT conformations, such states might play an important role in heparin binding. 'Generalized correlation' matrices revealed possible paths of allosteric signal propagation to the binding sites for the target proteases, factors Xa and IXa. Enhanced MD simulations of ligand binding to AT may assist the design of new anticoagulant drugs.Communicated by Ramaswamy H. Sarma.

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