Diversity in Molecular Recognition of Sulfated Oligohyaluronan Derivatives by Proteins of the Extracellular Matrix as Key for Their Binding Affinity

Session: 
PS2 Poster session 2 Even numbers
Code: 
P196
Location (hall): 
Foyer
Start/end time: 
Tuesday, July 2, 2019 - 15:45 to 17:15
Gloria
Ruiz-Gómez

Gloria Ruiz-Gómez1, Sebastian Köhling2, Joanna Blaszkiewicz2, María Isabel Fernández-Bachiller2, Katharina Lemmnitzer3, Jürgen Schiller3, Jörg Rademann2, M. Teresa Pisabarro1

1Structural Bioinformatics, BIOTEC TU Dresden, Tatzberg 47-51 , 01307 Dresden, Germany, 2Institute of Pharmacy – Medicinal Chemistry, Freie Universität Berlin, Königin-Luise-Str. 2+4 , 14195 Berlin, Germany, 3Institute of Medical Physics and Biophysics, University of Leipzig, Härtelstr. 16/18, 04107 Leipzig, Germany

The molecular recognition of sulfated glycosaminoglycans (GAGs) by a variety of proteins in the extracellular matrix (ECM) is crucial for physiological processes such as tissue hemostasis and repair, cell growth and cell-migration [1]. Therefore, chemically modified sulfated GAG derivatives constitute relevant molecules for the engineering of innovative biomaterials with application in tissue regenerative medicine.

The molecular recognition properties of several defined sulfated oligohyaluronan (sHA) derivatives differing in length, sulfation pattern and anomeric functionalization toward a set of regulatory proteins (i.e. interleukin 8 (IL-8), interleukin 10 (IL-10), bone morphogenic protein 2 (BMP-2) and Sclerostin) has been investigated by molecular modeling and dynamics (MD) simulations in combination with experimental binding techniques (i.e. fluorescence polarization competition assay and isothermal titration calorimetry) [2]. Binding affinity of sHA to the investigated protein targets increased with the GAG sulfation degree. Furthermore, functionalization of the anomeric center of the sHA with a large amphiphilic fluorophore or by a polyethylene glycol spacer in a dimeric GAG led to the highest affinities. Molecular docking and MD studies predicted a diversity of GAG binding sites and modes to the studied ECM regulatory proteins. Such diversity in recognition showed a high correlation with the binding affinities experimentally assessed. The generated molecular models provide insights on how certain GAG functionalities may influence their protein recognition. Thus, the high binding affinities of defined sHA modified at the anomeric center with large fluorophores are found to be not only a consequence of enhancing interactions with the target protein, but such modification is also observed to strongly alter recognition by directing the molecule toward other regions of the protein in a target-dependent manner. The outcome of this work can be used for future engineering of new customized biomaterials.

References: 
  1. J. D. Esko and R. J. Linhardt, in Essentials of Glycobiology, eds. A. Varki, R. D. Cummings, J. D. Esko, H. H. Freeze, P. Stanley, C. R. Bertozzi, G. W. Hart and M. E. Etzler, Cold Spring Harbor Laboratory Press The Consortium of Glycobiology Editors, La Jolla, California, Cold Spring Harbor (NY), 2009.
  2. Köhling, S.; Blaszkiewicz, J.; Ruiz-Gómez, G.; Fernández-Bachiller, M. I.; Lemmnitzer, K.; Panitz, N.; Beck-Sickinger, A. G.; Schiller,J.; Pisabarro, M. T.; Rademann, J. “Syntheses of defined sulfated oligohyaluronans reveal structural effects, diversity and thermodynamics of GAG–protein binding.” Chem. Sci. 2019, 10, 866-878.

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