Modeling of hyaluronan random coils in electrolyte solutions and hyaluronan-protein interactions using the molecular-dynamics methods

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F70883521%3A28110%2F17%3A63517193" target="_blank" >RIV/70883521:28110/17:63517193 - isvavai.cz</a>

Výsledek na webu

—

DOI - Digital Object Identifier

—

Jazyk výsledku

angličtina

Název v původním jazyce

Modeling of hyaluronan random coils in electrolyte solutions and hyaluronan-protein interactions using the molecular-dynamics methods

Popis výsledku v původním jazyce

Hyaluronan, an alternating copolymer of glucuronic acid and N-acetylglucosamine of the formula [4)-β-D-GlcpA-(13)-β-D-GlcpNAc-(1]n, is a biologically active polysaccharide occurring in connective tissues, especially the synovial fluid, vitreous fluid of eyes, umbilical cords and in chicken combs. Its function consists not only in being an important construction material of the extracellular matrix, but also in regulation of various molecular processes. In addition, thanks to its solubility and biocompatibility it is an attractive biotechnological material possessing potential applications in the field of drug-delivery systems and artificial-tissue scaffolds. Hence, hyaluronan has been studied intensely during the last decades, both experimentally and theoretically. The method of molecular dynamics is one of the key techniques that can be used for all-atom modelling of hyaluronan molecules. In the past it was used mainly to simulate rather short oligosaccharides of hyaluronan and to deduce the properties of larger molecules using the general models of polymer physics. We have extended this model to considerably longer oligosaccharides comparable with the expected persistence length of the polymer. Therefore, we carried out the equilibrium simulations of 48-monosaccharides long molecules of hyaluronan in various electrolyte environments differing mutually in the kind and concentration of the used salt. For each environment a statistically significant sets of macromolecules of different molecular weight was constructed connecting randomly chosen pieces of the simulated oligosaccharides from different frames of the equilibrated part of the simulation. Interactions of distant residues within the chain were neglected in the model. The individual pieces were connected in accord with the statistics of the dihedral-angles values at the glycosidic bonds occurring throughout the relevant part of the simulation. Macromolecules modeled this way showed an excellent agreement with experimental data of various sources regarding the dependence of the radius of gyration on the molecular weight up to the MDa size. In addition, we calculated also the dependence of the radius of gyration on the electrolyte concentration and obtained a trend well agreeing with the experimental data, i.e. the growth of Rg with decreasing electrolyte concentration. The persistence lengths of the macromolecules grow accordingly. Hence, the proposed method is suitable to construct all-atom models of hyaluronan (and, eventually, other polysaccharide) macromolecules and to predict their properties in different environments. The model indicates a low influence of the electrostatic interactions of the carboxylate groups and the interactions of distant residues within the chain. Simultaneously, we are using molecular-dynamics methods in order to identify hyaluronan binding sites on the molecules of hyaladherins, their protein binding partners. On a model of TSG-6 protein we have found a binding site for rather a long hyaluronan oligosaccharide that might play a role in the conformation stability of this two-domain protein. As a future perspective, we plan to study larger systems of hyaluronan and interacting proteins combining the classical and coarse-grained molecular dynamics methods in order to investigate more complex biochemical processes.

Název v anglickém jazyce

Modeling of hyaluronan random coils in electrolyte solutions and hyaluronan-protein interactions using the molecular-dynamics methods

Popis výsledku anglicky

Hyaluronan, an alternating copolymer of glucuronic acid and N-acetylglucosamine of the formula [4)-β-D-GlcpA-(13)-β-D-GlcpNAc-(1]n, is a biologically active polysaccharide occurring in connective tissues, especially the synovial fluid, vitreous fluid of eyes, umbilical cords and in chicken combs. Its function consists not only in being an important construction material of the extracellular matrix, but also in regulation of various molecular processes. In addition, thanks to its solubility and biocompatibility it is an attractive biotechnological material possessing potential applications in the field of drug-delivery systems and artificial-tissue scaffolds. Hence, hyaluronan has been studied intensely during the last decades, both experimentally and theoretically. The method of molecular dynamics is one of the key techniques that can be used for all-atom modelling of hyaluronan molecules. In the past it was used mainly to simulate rather short oligosaccharides of hyaluronan and to deduce the properties of larger molecules using the general models of polymer physics. We have extended this model to considerably longer oligosaccharides comparable with the expected persistence length of the polymer. Therefore, we carried out the equilibrium simulations of 48-monosaccharides long molecules of hyaluronan in various electrolyte environments differing mutually in the kind and concentration of the used salt. For each environment a statistically significant sets of macromolecules of different molecular weight was constructed connecting randomly chosen pieces of the simulated oligosaccharides from different frames of the equilibrated part of the simulation. Interactions of distant residues within the chain were neglected in the model. The individual pieces were connected in accord with the statistics of the dihedral-angles values at the glycosidic bonds occurring throughout the relevant part of the simulation. Macromolecules modeled this way showed an excellent agreement with experimental data of various sources regarding the dependence of the radius of gyration on the molecular weight up to the MDa size. In addition, we calculated also the dependence of the radius of gyration on the electrolyte concentration and obtained a trend well agreeing with the experimental data, i.e. the growth of Rg with decreasing electrolyte concentration. The persistence lengths of the macromolecules grow accordingly. Hence, the proposed method is suitable to construct all-atom models of hyaluronan (and, eventually, other polysaccharide) macromolecules and to predict their properties in different environments. The model indicates a low influence of the electrostatic interactions of the carboxylate groups and the interactions of distant residues within the chain. Simultaneously, we are using molecular-dynamics methods in order to identify hyaluronan binding sites on the molecules of hyaladherins, their protein binding partners. On a model of TSG-6 protein we have found a binding site for rather a long hyaluronan oligosaccharide that might play a role in the conformation stability of this two-domain protein. As a future perspective, we plan to study larger systems of hyaluronan and interacting proteins combining the classical and coarse-grained molecular dynamics methods in order to investigate more complex biochemical processes.

Druh

O - Ostatní výsledky

CEP obor

—

OECD FORD obor

10404 - Polymer science

Projekt

—

Návaznosti

S - Specificky vyzkum na vysokych skolach

Rok uplatnění

2017

Kód důvěrnosti údajů

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