Probing the effect of polyethene glycol on the adsorption mechanisms of Gem on the hexagonal boron nitride as a highly efficient polymer-based drug delivery system: DFT, classical MD and Well-tempered Metadynamics simulations.

The stability of Gemcitabine (Gem) anticancer drug on the hexagonal boron nitride (h-BN) and functionalized h-BN with polyethylene glycol (PEG-h-BN) as drug delivery carriers (DDSs) is investigated. The density functional theory (DFT) calculations, molecular dynamics (MD) simulation and Metadynamics simulations are used to study the nature of h-BN-Gem interactions as well as the role of PEG group to increase the efficiency of the DDS. The results of DFT calculations reveal that the drug physisorbed on the h-BN surface through the formation of π-π stacking with an adsorption energy range -15.08 kJ/mol to -90.74 kJ/mol. Moreover, the obtained results show that the grafting the PEG group to h-BN cause to π-π stacking is reinforced by the formation of strong HBs and leads to increase adsorption energy about 20%. There is a good agreement between DFT calculation and MD simulation results. Also, The MD simulations demonstrate in adsorption of the drug on the carriers, the contribution of van der Waals energy is more than the electrostatic energy. The well-tempered metadynamics simulations are performed to find the free energy surface (FES) of the studied systems. The FES for the Gem/h-BN and Gem/PEG-h-BN interfaces show the global minimum at around 3.0-6.0 Å and 1.2 Å, respectively. The orientational analysis proves that the global minimum can be related to the formation of π-π stacking and HB interaction.