Adsorption of methotrexate on hyaluronic acid: A comparative DFT and molecular dynamics simulation insights

Abstract

The potential of hyaluronic acid (HA) as a carrier for methotrexate (MTX) has been explored by quantum mechanics calculations in gaseous and water phases by density functional theory (DFT) and an all-atom molecular dynamics (MD) simulation in an explicit aqueous solvent. MTX adsorption on HA was systematically computed to analyze the bond formation, charge transfer, and binding energies between them in both gaseous and aqueous phases. The DFT analysis revealed polar covalent and electrostatic interactions between HA and MTX in both the gas and water mediums. In addition, according to calculations using natural bond orbitals (NBO), there is a shift of charges from σ and n orbitals in carbon, nitrogen, hydrogen, and oxygen atoms of MTX to n* and σ orbitals in oxygen and hydrogen atoms of HA, with appreciable charge-transfer energies in both the gas and water phases. Due to the solvent effects, the binding energy of the most stable HA-MTX complex was lower in the aqueous phase compared to the gas phase. Subsequently, a MD simulation in the water phase was performed to assess the stability of the complex derived from DFT calculations. The simulation validated the stability of the HA-MTX complex and revealed that MTX is most likely adsorbed onto the top edge of HA via a physical adsorption mechanism. These results indicate that HA may be a viable and efficient carrier for MTX in therapeutic applications.