How PEGylation Enhances the Stability and Potency of Insulin: A Molecular Dynamics Simulation

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• 作者：Cheng Yang ; Diannan Lu ; Zheng Liu
• 刊名：Biochemistry
• 出版年：2011
• 出版时间：April 5, 2011
• 年：2011
• 卷：50
• 期：13
• 页码：2585-2593
• 全文大小：1220K
• 年卷期：v.50,no.13(April 5, 2011)
• ISSN：1520-4995

文摘

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.