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Molecular Insight into the Steric Shielding Effect of PEG on the Conjugated Staphylokinase: Biochemical Characterization and Molecular Dynamics Simulation
Mu, Qimeng1,2; Hu, Tao1; Yu, Jingkai1
2013-07-18
Source PublicationPLOS ONE
Volume8Issue:7Pages:68559
AbstractPEGylation is a successful approach to improve potency of a therapeutic protein. The improved therapeutic potency is mainly due to the steric shielding effect of PEG. However, the underlying mechanism of this effect on the protein is not well understood, especially on the protein interaction with its high molecular weight substrate or receptor. Here, experimental study and molecular dynamics simulation were used to provide molecular insight into the interaction between the PEGylated protein and its receptor. Staphylokinase (Sak), a therapeutic protein for coronary thrombolysis, was used as a model protein. Four PEGylated Saks were prepared by site-specific conjugation of 5 kDa/20 kDa PEG to N-terminus and C-terminus of Sak, respectively. Experimental study suggests that the native conformation of Sak is essentially not altered by PEGylation. In contrast, the bioactivity, the hydrodynamic volume and the molecular symmetric shape of the PEGylated Sak are altered and dependent on the PEG chain length and the PEGylation site. Molecular modeling of the PEGylated Saks suggests that the PEG chain remains highly flexible and can form a distinctive hydrated layer, thereby resulting in the steric shielding effect of PEG. Docking analyses indicate that the binding affinity of Sak to its receptor is dependent on the PEG chain length and the PEGylation site. Computational simulation results explain experimental data well. Our present study clarifies molecular details of PEG chain on protein surface and may be essential to the rational design, fabrication and clinical application of PEGylated proteins.
SubtypeArticle
WOS HeadingsScience & Technology
Indexed BySCI
Language英语
WOS KeywordSITE-SPECIFIC PEGYLATION ; POLYETHYLENE-GLYCOL ; PLASMINOGEN ACTIVATION ; CHEMICAL-MODIFICATION ; DRUG-DELIVERY ; PROTEIN ; HEMOGLOBIN ; IMMUNOGENICITY ; BIOACTIVITY ; STABILITY
WOS Research AreaScience & Technology - Other Topics
WOS SubjectMultidisciplinary Sciences
WOS IDWOS:000324146200020
Citation statistics
Cited Times:34[WOS]   [WOS Record]     [Related Records in WOS]
Document Type期刊论文
Identifierhttp://ir.ipe.ac.cn/handle/122111/13563
Collection研究所(批量导入)
Affiliation1.Chinese Acad Sci, Inst Proc Engn, Natl Key Lab Biochem Engn, Beijing, Peoples R China
2.Univ Chinese Acad Sci, Beijing, Peoples R China
Recommended Citation
GB/T 7714
Mu, Qimeng,Hu, Tao,Yu, Jingkai. Molecular Insight into the Steric Shielding Effect of PEG on the Conjugated Staphylokinase: Biochemical Characterization and Molecular Dynamics Simulation[J]. PLOS ONE,2013,8(7):68559.
APA Mu, Qimeng,Hu, Tao,&Yu, Jingkai.(2013).Molecular Insight into the Steric Shielding Effect of PEG on the Conjugated Staphylokinase: Biochemical Characterization and Molecular Dynamics Simulation.PLOS ONE,8(7),68559.
MLA Mu, Qimeng,et al."Molecular Insight into the Steric Shielding Effect of PEG on the Conjugated Staphylokinase: Biochemical Characterization and Molecular Dynamics Simulation".PLOS ONE 8.7(2013):68559.
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