Glycosaminoglycans (GAGs) represent a particular class of linear anionic periodic polysaccharides made up of repetative disaccharide units which could be sulfated in different positions and therefore determine their structural and functional properties. GAGs are located in the extracellular matrix of the cell, where they participate in many cell signaling processes via interactions with their protein targets such as cytokines and growth factors. Despite the high biological relevance of these interactions, molecular mechanisms underlying them are not well understood due to the challenging nature of these molecules for the experimental analysis. Therefore, modeling is very useful to complement the experiment and to provide new insights in protein-GAG systems. Although molecular modeling of protein-GAG interactions also experiences difficulties due to the scarcity of the computational methods for these systems in comparison to other biomolecular complexes, we established and successfully applied molecular docking and molecular dynamics-based protocols to the complexes of GAGs with the following protein targets: IL-8, SDF-1, VEGF, FGF1, sclerostin, TIMP-3, BMP-2, cathepsin K and others (most representative publications are provided below in References). Such modeling studies exploiting the available corresponding experimental data allowed to complement, explain and rationally guide the further experimental analysis.
Here, we present an interdisciplinary work, where we provide modeling insights into the molecular mechanisms underlying the role of GAGs in cell signaling processes, where several protein targets are involved: CXCL-14, VEGF and cathepsin K. Our results contribute to deepening the general understanding of the molecular interactions in protein-GAG systems and, in perspective, could be very useful for the development of novel approaches within the area of regenerative medicine.
- Bojarski K.K., Sieradzan A.K., Samsonov S.A. Molecular Dynamics Insights into Protein-Glycosaminoglycan Systems from Microsecond-Scale Simulations. Biopolymers. 2019.
- Uciechowska-Kaczmarzyk U., Babik S., Zsila F., Bojarski K.K., Beke-Somfai T., Samsonov S.A. Molecular Dynamics-Based Model of VEGF-A and Its Heparin Interactions. JMGM. 2018.
- Nordsieck K., Baumann L., Hintze V., Pisabarro M.T., Schnabelrauch M., Beck-Sickenger A.G., Samsonov S.A. The effect of interleukin-8 truncations on its interactions with glycosaminoglycans. Biopolymers. 2018.
- Babik S., Samsonov S.A., Pisabarro M.T. Computational drill down on FGF1-heparin interactions through methodological evaluation. Glycoconj J, 2017.
- Rother S., Samsonov S.A., Hofmann T., Blaszkiewicz J., Köhling S., Schnabelrauch M., Möller S., Rademann J., Kalkhof S., von Bergen M., Pisabarro M.T., Scharnweber D., Hintze V. Structural and functional insights into the interaction of sulfated glycosaminoglycans with tissue inhibitor of metalloproteinase-3 - a possible regulatory role on extracellular matrix homeostasis. Acta Biomaterialia. 2016.
- Panitz N., Theisgen S., Samsonov S.A., Gehrcke J.-P., Baumann L., Pisabarro M.T., Bellmann-Sickert K., Rademann J., Huster D., Beck-Sickinger A. The Structural Investigation of Glycosaminoglycan Binding to CXCL12 Displays Distinct Interaction Sites. Glycobiology, 2016.
- Hintze V., Samsonov S., Anselmi M., Moeller S., Becher J., Schnabelrauch M., Scharnweber D., Pisabarro M.T. Sulfated glycosaminoglycans exploit the conformational plasticity of bone morphogenetic protein-2 (BMP-2) and alter the interaction profile with its receptor. Biomacromolecules, 2014.
- Sage J., Mallevre F., Barbarin-Costes F., Samsonov S., Gehrcke J.-P., Pisabarro M. T., Perrier E., Schnebert S., Roget A., Livache T., Nizard C., Lalmanach G., Lecaille F. Binding of chondroitin 4-sulfate to cathepsin S regulates its enzymatic activity. Biochemistry, 2013.
- Salbach-Hirsch J., Kraemer J., Rauner M., Samsonov S.A., Pisabarro M.T., Moeller S., Schnabelrauch M., Scharnweber D., Hofbauer L.C, Hintze V. The promotion of osteoclastogenesis by sulfated hyaluronan through interference with osteoprotegerin and receptor activator of NF-κB ligand/osteoprotegerin complex formation. Biomaterials, 2013.
- Pichert A., Samsonov S.A., Theisgen S., Thomas L., Baumann L., Schiller J., Beck-Sickinger A.G., Huster D., Pisabarro M.T. Characterization of the Interaction of Interleukin-8 with Hyaluronan, Chondroitin Sulfate, Dermatan Sulfate, and Their Sulfated Derivatives by Spectroscopy and Molecular Modelling. Glycobiology, 2012.