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.