Molecular dynamics analysis of hyaluronic acid–albumin complexes: effect of the HSA-to-HA ratio on structure and stability

Abstract

Hyaluronic acid (HA) and human serum albumin (HSA) are essential components of synovial fluid, playing critical roles in joint lubrication and function. This study examines the influence of the HSA-to-HA ratio on the structural characteristics and stability of their complexes using molecular dynamics simulations. The simulations show that the HA-to-HSA ratio significantly affects the frequency and nature of intermolecular interactions that stabilize the HA–HSA complexes. When the HSA content is lower than HA, the HA chain samples a broader range of conformations and forms an extensive network of hydrogen bonds and hydrophobic interactions with HSA. In HSA-rich systems, HA shows reduced conformational fluctuations and forms fewer overall contacts with albumin. Notably, the specific HSA subdomains involved in stabilizing the complexes also depend on the HA-to-HSA ratio. At HA-rich compositions, subdomain IB shows the highest average number of HA–HSA contacts. At higher protein content, subdomain IA shows the highest average contact count. Interaction-energy analysis indicates that complexes with higher HA content are more stable, consistent with previous observations on the rheological properties of HA–albumin hydrogels. The study underscores the importance of hydrophobic interactions, alongside hydrogen bonding, in stabilizing these biomolecular complexes. Additionally, the analysis of water interactions is consistent with a reduced HA contribution to hydration lubrication as the HSA content increases, alongside increased hydration of specific HSA residues.