Volume 3, Issue 2, June 2019, Page: 37-44
Thermostabilization of Hyaluronidase by Chondroitin Ligands in Molecular Docking
Alexander Vasilievich Maksimenko, Institute of Experimental Cardiology, National Research Medical Center for Cardiology, Moscow, Russia
Robert Shavlovich Beabealashvili, Institute of Experimental Cardiology, National Research Medical Center for Cardiology, Moscow, Russia
Received: May 28, 2019;       Accepted: Jul. 15, 2019;       Published: Jul. 30, 2019
DOI: 10.11648/j.ccr.20190302.14      View  29      Downloads  7
Speedup of present high-molecular drug derivatives developments is based on the computational methods harmonic application. Such glycosidase as hyaluronidase has been functionated among multifarious glycosaminoglycan microenvironment in blood circulation of organism. It is important for elucidation of action mechanism of biosystem components (on vascular wall) and productive obtaining of hyaluronidase derivatives of cardiological destination the using of computer aided calculations for investigation of protein-glycosaminoglycan interactions. The aim of our study became the molecular docking fulfillment for 3D model of bovine testicular hyaluronidase with short-chain dimer and trimer chondroitin ligands. We used the molecular docking of hyaluronidase with chondroitin ligands for theoretical determination of biocatalyst conformational stability. At temperatures higher than 300 K free/native hyaluronidase (without ligands) displayed conformational transitions leading to its inactivation. Predominant manifestation of these transitions was an irreversible attraction developing between the protein area proximate to Glu-105, on the one hand, and to Arg-59 and Arg-96, on the other. Lowering of temperature did not restore the initial 3D structure of hyaluronidase. Binding of chondroitin ligands at ch 6, ch 3 and ch 1 sites stabilized the enzyme, increasing its denaturation temperature by 10°C. The highest degree of stabilization was achieved after chondroitin binding to ch 6. This effect was higher than that for chondroitin sulfate trimers concerning the enzyme inhibition by heparin tetramer, which requires binding of 4-5 chondroitin sulfate ligands to the enzyme surface. Molecular docking of 3D model of bovine testicular hyaluronidase with chondroitin dimers and trimers has revealed eight sites for their binding to the enzyme surface. At biological concentrations of these ligands the most important binding sites for them are ch 6, ch 3 and ch 1. Binding at these sites induces a reversible deformation of the protein 3D structure. Interactions between 3D model of bovine hyaluronidase with chondroitin ligands are based predominantly on electrostatic forces. Chondroitin ligands stabilized 3D structure of hyaluronidase after binding predominantly at chondroitin 6 as well as chondroitin 3 and chondroitin 1 positions and their effect was higher than chondroitin sulfate upon enzyme inhibition by heparin tetramer. Stabilizing effects of chondroitin and chondroitin sulfate ligands are fundamental for further direct theoretical comparative investigation of impact produced by these ligands.
Bovine Testicular Hyaluronidase, Protein Space Structure, Glycosaminoglycan Ligands, Chondroitin, Molecular Docking, Enzyme Structure Stabilization
To cite this article
Alexander Vasilievich Maksimenko, Robert Shavlovich Beabealashvili, Thermostabilization of Hyaluronidase by Chondroitin Ligands in Molecular Docking, Cardiology and Cardiovascular Research. Vol. 3, No. 2, 2019, pp. 37-44. doi: 10.11648/j.ccr.20190302.14
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Maksimenko AV. Development and application of targeted therapeutic protein conjugates. Russ. J. Gen. Chem. 2014; 84 (2): 357-363. Doi: 10. 1134/S1070363214020376.
Maksimenko AV. Results and achievements in the engineering of pharmacological enzymes for clinical application. Med. Res. Arch. 2018; 6 (1): 1-13. http://journals.ke-i.org/index. php/mra
Maksimenko AV. Translational research into vascular wall function: regulatory effects of systemic and specific factors. J. Transl. Sci. 2017; 3 (2): 1-10. Doi: 10. 15761/JTS. 1000180.
Almond A. Multiscale modeling of glycosaminoglycan structure and dynamics: current methods and challenges. Curr. Opin. Struct. Biol. 2018; 50: 58-64. http://doi.org/10.1016/j.sbi.2017.11.008.
Sankaranarayanan NV, Nagarajan B, Desai UR. So you think computational approaches to understanding glycosaminoglycan-protein interactions are too dry and too rigid? Think again! Curr. Opin. Struct. Biol. 2018; 50: 91-100. http//doi.org/10.1016/j.sbi.2017.12.004
Hage KE, Brickel S, Hermalin S, Gaulier G, Schmidt C, Bonacina L, van Keulen SG, Bhattacharyya S, Chergui M, Hamm P, Rothlisberger U, Wolf J-P, Meuwly M. Implication of short time scale dynamics on long time process. Struct. Dyn. 2017; 4: 061507. http://doi.org/10.1063/1/499648
Meng X-Y, Zhang H-X, Mezei M, Cui M. Molecular docking: a powerful approach for structure-based drug discovery. Curr. Comput. Aided Drug Des. 2011; 7 (2): 146-157.
Reitsma S, Slaaf DW, Vink H, van Zandvoort MAMJ, onde Egbrink MGA. The endotheliumglycocalyx: composition, function, and visualization. Pflügers Arch. 2007; 454: 345-359.
Broekhuisen LN, Moojij HL, Kastelein JJ, Stroes ESG, Vink H, Nieuwdorp M. Endothelial glycocalyx as potential diagnostic and therapeutic target in cardiovascular disease. Curr. Opin. Lipidol. 2009; 20: 57-62.
Maksimenko AV, Schechilina YV, Tischenko EG. Resistance of dextran-modified hyaluronidase to inhibition by heparin. Biochemistry (Moscow). 2001; 66 (4): 456-463.
Maksimenko AV, Schechilina YV, Tischenko EG. Role of the glycosaminoglycan microenvironment of hyaluronidase in regulation of its endoglycosidase activity. Biochemistry (Moscow). 2003; 68 (8): 862-868.
Meyer K, Rapport MM. The hydrolysis of chondroitin sulfate by testicular hyaluronidase. Arch. Biochem. 1950; 27 (2): 287-293.
Hoffman P, Meyer K, Linker A. Transglycosylation during the mixed digestion of hyaluronic acid and chondroitin sulfate by testicular hyaluronidase. J. Biol. Chem. 1956; 219 (2): 653-663.
Maksimenko AV, Beabealashvili RS. Conformational transitions in 3D model of bovine testicles hyaluronidase during molecular docking with glycosaminoglycan ligands. Russ. J. Bioorgan. Chem. 2018; 44 (2): 165-172.
Maksimenko AV Turashev AD, Beabealashvili RS. Stratification of chondroitin sulfate binding sites in 3D-model of bovine testicular hyaluronidase and effective size of glycosaminoglycan coat of the modified protein. Biochemistry (Moscow). 2015; 80 (3): 284-295.
Pettersen EF, Goddard TD, Huang CC, Couch GS, Greenblatt DM, Meng EC, Ferrin TE. UCSF Chimera – a visualization system for exploratory research and analysis. J. Comput. Chem. 2004; 25 (13): 1605-1612.
Sanner MF, Olson AJ, Spehner JC. Reduced surface: an efficient way to compute molecular surfaces. Biopolymers. 1996; 38 (3): 305-320.
Lang PT, Brozell SR, Mukherjee S, Pettersen EF, Meng EC, Thomas V, Rizzo RC, CaseDA, James TL, Kuntz ID. DOCK 6: combining techniques to model RNA-small molecule complexes. RNA. 2009; 15 (6): 1219-1230.
Yang J, Chi L. Characterization of structural motifs for interactions between lycosaminoglycans and proteins. Carbohyd. Res. 2017; 452: 54-63.
Maksimenko AV, Beabealashvili RS. Effect of the hyaluronidase microenvironment on the enzyme structure-function relationship and computational study in silico of the molecular docking of chondroitin sulfate and heparin short fragments to hyaluronidase. Russ. Chem. Bull. Intl. Ed. 2018; 67 (4): 1-11.
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