Binding of hyaluronan and its neutral analog by TSG-6 protein studied by molecular dynamics

Kód výsledku v IS VaVaI

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Výsledek na webu

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DOI - Digital Object Identifier

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Jazyk výsledku

angličtina

Název v původním jazyce

Binding of hyaluronan and its neutral analog by TSG-6 protein studied by molecular dynamics

Popis výsledku v původním jazyce

Hyaluronic acid (HA, hyaluronan), an alternating co-polymer of glucuronic acid and N-acetylglucosamine ([4)-β-D-GlcpA-(13)-β-D-GlcpNAc-(1]n), is a major component of extracellular matrix of animal connective tissues. Besides being only a passive construction material, it also plays roles in numerous signaling cascades and is thus involved in inflammation, progression of various diseases including cancer, and wound healing. In these processes HA interacts with several membrane-bound and soluble protein receptors called hyaladherins. The former group contains mainly proteins CD44, LYVE-1 and RHAMM, the latter e.g. TSG-6. In spite of several decades of research, many of the signaling cascades exploiting HA are still not fully understood1. Molecular-dynamics simulations can therefore help us to explain the structural features of the HA-hyaladherin complexes and the relations between their structure and function. TSG-6 is an intensively studied molecule whose structure is known from numerous NMR experiments that indicate the interaction of this protein with HA as well as another glycosaminoglycan, heparin and chondroitinsulfate2. In this study we simulated the binding of HA oligosaccharides by TSG-6 and we identified two binding sites of this molecule. One of them is identical with the sites described previously3, but the other one, so far unknown, partially overlaps with the less stable binding site of heparin4 and also for chondroitinsulfate2. In order to evaluate the specificity of the binding sites for HA and charged oligosaccharides in general, we carried out analogous simulations with the neutral HA analog containing the glucuronic acid residue instead of glucose5. They showed that this molecule can be bound by both these sites. However, the stabilization Gibbs energy determined by the umbrella sampling method that in the first site the analog binds much more weakly than HA, while in the other site the analog binding is even more stable than that of HA. The results thus show that, while the first binding site is quite specific for HA, the second one is able of binding various oligosaccharides and the binding is independent of the negative charge of the ligand. It indicates the possibility of designing artificial ligands of hyaladherins with a potential pharmaceutical application.

Název v anglickém jazyce

Binding of hyaluronan and its neutral analog by TSG-6 protein studied by molecular dynamics

Popis výsledku anglicky

Hyaluronic acid (HA, hyaluronan), an alternating co-polymer of glucuronic acid and N-acetylglucosamine ([4)-β-D-GlcpA-(13)-β-D-GlcpNAc-(1]n), is a major component of extracellular matrix of animal connective tissues. Besides being only a passive construction material, it also plays roles in numerous signaling cascades and is thus involved in inflammation, progression of various diseases including cancer, and wound healing. In these processes HA interacts with several membrane-bound and soluble protein receptors called hyaladherins. The former group contains mainly proteins CD44, LYVE-1 and RHAMM, the latter e.g. TSG-6. In spite of several decades of research, many of the signaling cascades exploiting HA are still not fully understood1. Molecular-dynamics simulations can therefore help us to explain the structural features of the HA-hyaladherin complexes and the relations between their structure and function. TSG-6 is an intensively studied molecule whose structure is known from numerous NMR experiments that indicate the interaction of this protein with HA as well as another glycosaminoglycan, heparin and chondroitinsulfate2. In this study we simulated the binding of HA oligosaccharides by TSG-6 and we identified two binding sites of this molecule. One of them is identical with the sites described previously3, but the other one, so far unknown, partially overlaps with the less stable binding site of heparin4 and also for chondroitinsulfate2. In order to evaluate the specificity of the binding sites for HA and charged oligosaccharides in general, we carried out analogous simulations with the neutral HA analog containing the glucuronic acid residue instead of glucose5. They showed that this molecule can be bound by both these sites. However, the stabilization Gibbs energy determined by the umbrella sampling method that in the first site the analog binds much more weakly than HA, while in the other site the analog binding is even more stable than that of HA. The results thus show that, while the first binding site is quite specific for HA, the second one is able of binding various oligosaccharides and the binding is independent of the negative charge of the ligand. It indicates the possibility of designing artificial ligands of hyaladherins with a potential pharmaceutical application.

Druh

O - Ostatní výsledky

CEP obor

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OECD FORD obor

10610 - Biophysics

Projekt

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Návaznosti

S - Specificky vyzkum na vysokych skolach

Rok uplatnění

2018

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů