10.1021/bi101926u.s001 Cheng Yang Cheng Yang Diannan Lu Diannan Lu Zheng Liu Zheng Liu How PEGylation Enhances the Stability and Potency of Insulin: A Molecular Dynamics Simulation American Chemical Society 2011 surface area PEG polymers drug potency chain lengths circulation life Molecular Dynamics SimulationWhile protein drug chain length water molecules kidney filtration simulation results hydrogen bonds protein pharmaceuticals immunogenic side effects interaction PEGylation Enhances protein surface PEGylated protein pharmaceuticals dynamics simulation annealing procedure structure analyses 2011-04-05 00:00:00 Journal contribution https://acs.figshare.com/articles/journal_contribution/How_PEGylation_Enhances_the_Stability_and_Potency_of_Insulin_A_Molecular_Dynamics_Simulation/2669572 While the effectiveness of PEGylation in enhancing the stability and potency of protein pharmaceuticals has been validated for years, the underlying mechanism remains poorly understood, particularly at the molecular level. A molecular dynamics simulation was developed using an annealing procedure that allowed an all-atom level examination of the interaction between PEG polymers of different chain lengths and a conjugated protein represented by insulin. It was shown that PEG became entangled around the protein surface through hydrophobic interaction and concurrently formed hydrogen bonds with the surrounding water molecules. In addition to enhancing its structural stability, as indicated by the root-mean-square difference (rmsd) and secondary structure analyses, conjugation increased the size of the protein drug while decreasing the solvent accessible surface area of the protein. All these thus led to prolonged circulation life despite kidney filtration, proteolysis, and immunogenic side effects, as experimentally demonstrated elsewhere. Moreover, the simulation results indicated that an optimal chain length exists that would maximize drug potency underpinned by the parameters mentioned above. The simulation provided molecular insight into the interaction between PEG and the conjugated protein at the all-atom level and offered a tool that would allow for the design of PEGylated protein pharmaceuticals for given applications.