Extending the Martini 3 Coarse-Grained Force Field to Hyaluronic Acid

Hyaluronan, also known as hyaluronic acid, is a large glycosaminoglycan composed of repeating disaccharide units. It plays a crucial role in providing structural support, hydration, and facilitating cellular processes in connective tissue, skin, and the extracellular matrix in biological systems. We present a coarse-grained (CG) model of hyaluronic acid (HA) and its constituent residues, <i>N</i>-acetyl-d-glucosamine (GlcNAc) and glucuronic acid (GlcA), designed to be compatible with the Martini 3 force field. The model was validated against atomistic molecular dynamics simulations following standard procedures to ensure the accuracy of bonded interactions and, in the case of GlcNAc, the free energies of transfer between octanol and water. For the final HA model, we investigated its properties by simulating the self-assembly of HA chains at varying ion concentrations in solution and comparing the persistence length of single-chain HA with experimental data. We also studied the interactions of HA with lipid bilayers and various HA-binding proteins, demonstrating the ability of the model to accurately reproduce interactions with other biomolecules characteristic of natural biological systems. This extension of the carbohydrate-dedicated branch of the CG Martini 3 force field enables large-scale molecular dynamics simulations of HA-containing systems and contributes to a better understanding of the roles and functions of hyaluronan in natural biomolecular systems.