Protein Aggregation and Performance Optimization Based on Microconformational Changes of Aromatic Hydrophobic Regions
Wen, Lili1; Lyu, Man1; Xiao, Huashuai1; Lan, Hairong1; Zuo, Zhili2; Yin, Zongning1
2018-06-01
发表期刊MOLECULAR PHARMACEUTICS
ISSN1543-8384
卷号15期号:6页码:2257-2267
摘要Protein aggregation is a key concern in biopharmaceutical development and manufacturing. There is growing interest in understanding how the changes in protein microconformation affect the aggregation behavior. This study selected several representative proteins and first manipulated microconformational changes of the aromatic hydrophobic regions of proteins, especially tryptophan residues, by using amine or guanidine additives. The effects of the interactions between the additives and proteins on the aromatic hydrophobic regions could be grouped into three categories: exposure to solvent, burial into core, and no change. The microconformational parameters of the tryptophan residue, including fluorescence peak position (lambda(m)), degree of hydrolysis, solvent accessible surface area (SAS), and packing density (Den), were obtained by steady-state fluorescence spectroscopy, proteolysis coupled with electrophoresis, and molecular dynamics simulation. Furthermore, the aggregation degrees of globular proteins with distinct surface aromatic hydrophobilities under mechanical stress were investigated. A strong correlation was observed between protein aggregation and the microconformational changes of the aromatic hydrophobic regions incurred by amine or guanidine additives. Protein aggregation was enhanced when the aromatic hydrophobic regions were exposed to the solvent but suppressed when the additives led to burial of the aromatic hydrophobic regions with lower-polarity microenvironment. These findings shed light on the relationship between protein aggregation and molecular conformation and paved way for future preformulation studies of therapeutic proteins.
关键词Protein Aggregation Aromatic Hydrophobic Regions Amine Compounds Guanidine Compounds Microconformational Change
语种英语
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文献类型期刊论文
条目标识符http://ir.kib.ac.cn/handle/151853/61350
专题植物化学与西部植物资源持续利用国家重点实验室
作者单位1.Sichuan Univ, West China Sch Pharm, Key Lab Drug Targeting & Drug Delivery Syst, Chengdu 610041, Sichuan, Peoples R China
2.Chinese Acad Sci, Kunming Inst Bot, State Key Lab Phytochem & Plant Resources West Ch, Kunming 650201, Yunnan, Peoples R China
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Wen, Lili,Lyu, Man,Xiao, Huashuai,et al. Protein Aggregation and Performance Optimization Based on Microconformational Changes of Aromatic Hydrophobic Regions[J]. MOLECULAR PHARMACEUTICS,2018,15(6):2257-2267.
APA Wen, Lili,Lyu, Man,Xiao, Huashuai,Lan, Hairong,Zuo, Zhili,&Yin, Zongning.(2018).Protein Aggregation and Performance Optimization Based on Microconformational Changes of Aromatic Hydrophobic Regions.MOLECULAR PHARMACEUTICS,15(6),2257-2267.
MLA Wen, Lili,et al."Protein Aggregation and Performance Optimization Based on Microconformational Changes of Aromatic Hydrophobic Regions".MOLECULAR PHARMACEUTICS 15.6(2018):2257-2267.
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