Abstract
Hyaluronic acid (HA) has a wide range of biomedical applications including the formation of hydrogels, microspheres, sponges, and films. The modeling of HA to understand its behavior and interaction with other biomolecules at the atomic level is of considerable interest. The atomistic representation of long HA polymers for the study of the macroscopic structural formation and its interactions with other polyelectrolytes is computationally demanding. To overcome this limitation, we developed a coarse grained (CG) model for HA adapting the Martini scheme. A very good agreement was observed between the CG model and all-atom simulations for both local (bonded interactions) and global properties (end-to-end distance, a radius of gyration, RMSD). Our CG model successfully demonstrated the formation of HA gel and its structural changes at high salt concentrations. We found that the main role of CaCl2 is screening the electrostatic repulsion between chains. HA gel did not collapse even at high CaCl2 concentrations, and the osmotic pressure decreased, which agrees well with the experimental results. This is a distinct property of HA from other proteins or polynucleic acids which ensures the validity of our CG model. Our HA CG model is compatible with other CG biomolecular models developed under the Martini scheme, which allows for large-scale simulations of various HA-based complex systems.
Highlights
Hyaluronic acid (HA), called hyaluronan, is a linear anionic polysaccharide comprised of repeating disaccharide units of D-glucuronic acid (GlcA) and N-acetyl-D-glucosamine (GlcNAc) linked by alternating β(1–3) and β(1–4) glucosidic bonds [1]
HA can be chemically modified through conjugation and crosslinking polymerization processes, and its properties have been customized for several biomedical applications [2]
Polyelectrolyte gel swelling is the subject of numerous studies in polymer physics which demonstrate that minute changes in external conditions such as temperature, external electric field, solvent composition, and ionic strength can induce drastic changes in gel swelling properties [8]
Summary
Hyaluronic acid (HA), called hyaluronan, is a linear anionic polysaccharide comprised of repeating disaccharide units of D-glucuronic acid (GlcA) and N-acetyl-D-glucosamine (GlcNAc) linked by alternating β(1–3) and β(1–4) glucosidic bonds [1]. An interesting property of HA is that it keeps a liquid form in the physiological NaCl conditions, even under high CaCl2 concentrations, which is unusual for other biological polyelectrolytes Due to this property and the high biocompatibility of HA, it has been widely investigated for the development of hydrogel scaffolds for tissue engineering [3]. Different polyelectrolyte polymers have been studied in complex coacervate formation with HA. Martini-based models have been applied to understand the cross interactions of protein–polymer complex formations [21]. We developed and validated a CG model for HA based on the Martini scheme for modeling coarse-grained simulations, which will make it possible to perform greatly accelerated simulations for understanding events in HA polyelectrolyte complexation. AtrlaljethcteorAieAs wtrearjectthoerniecsonwveerretetdhetonCcoGntvraejretcetdortioesCG trabjaescetdoroiens tbhaeseCdGonmtahpepiCnGg smchaepmpiendgesscchriebmede dabeoscvrei.bTedheabporovbea. bTilhiteypdriosbtraibuiltitioyndsisfotrribthuetiobnosndfoerdthe botnerdmeds cteorumlds bceoucladlcbuelacteadlcufrloamtedthferosemotbhteasineeodbCtaGinetrdajCecGtotrriaesjewctohriciehswwihllicbhe wreiflelrbreedretfoerarsetdhetoAaAs the AAdisdtrisibtruitbiuontiso.nTsh. eThgemgxmdxisdtainstcaenpceropgrroagmrawmaws ausseudsetdo tcoalccaullcautelattheethbeobnodnddisdtrisibtruitbiuontisonbsetbweetewneen avaevreargaegdedCGCpGoinptosinotbstaoinbetadinbeydavbeyraagvinegrafgrionmg AfrAomsimAuAlatisoimnsu. lTathioenasn.gTlehseanadngdliehsedarnadl ddisithreibduratilons wedriestrciablucutiloantsedwebrye ucaslicnuglattheedgbmy uxsainnggltehepgromgxraamng.leSpecroognrdalmy,.aSercaonnddolym, agruaensdsofmorgbuoenssdfeodr bteornmdsedwas mtaedrme tsowoabstaminadineittioalopbatarianmientietirasl fpoarrraumnenteinrsgftohrerCunGnsinimg uthlaetiCoGnss.iTmhuelantieownsp. rTohbeabnielwitypdroisbtaribbiluittyions fodr ibsotrnibdulteionngsthfso,ranbgolneds, alenndgtdhish,edanragllsesw, earnedcadlcihueladtreadlsfrwomerethceaolcbutlaaitneedd fCroGmtrathjeectoobriteasin, ewdhiCchGare raevttCferheGarerajrecgecopdetraodrrtreaoiAsempsaA,oeswtndetdhhrisisiencthrgCwibaaGevrureeetdirroiaecsngfoteresnridbrtiineuAndutoAitoroodudnaesissslr.yttrthTiobuehuopCetbdiGoCtaantGdiesndisidnatritsoigobtrorudiortbeeidroudntutmoisco.aoenTtbcshtthahewi.enCeInaGrdeigcsdcoatiaoossnmetdrciomepbfuaabarttieecomthdwn.iswIsenmweintceahartsetctehhhceo,oefCmtcawGopmroarprieseassmderpatawosmtncitohedhf,tienrgs wedriestcriobnuttiinounosuusnltyiluapgdoaotdedmtaotcrhedwuacseotbhteaidniesdta. nce between the two sets of distributions until a good match was obtained
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