细胞穿膜肽的穿膜活性与序列特征的关系
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山东省生物物理重点实验室(德州学院),电子科技大学生命科学与技术学院生物信息学中心,山东省生物物理重点实验室(德州学院),德州学院 物理与电子信息学院;山东省生物物理重点实验室(德州学院)

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国家自然科学基金(31000324, 61271378, 11447004), 山东省自然科学基金(ZR2012CL09, ZR2014AL014, ZR2014JL006) 及山东省泰山学者资助项目


Relationship Between Cell Penetrating Peptides (CPPs) With Different Activities and Their Sequence Characteristics
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Key Laboratory of Biophysics of Shandong Dezhou University,Dezhou,Shandong,China The College of Physics and Electronic Information of Dezhou University,Dezhou,Shandong,China Center of Bioinformatics School of Life Science and Technology,University of Electronic Science and Technology of China,Chengdu,China,Center of Bioinformatics School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, China; Key Laboratory of Biophysics of Shandong Dezhou University,Dezhou,Shandong,China The College of Physics and Electronic Information of Dezhou University,Dezhou,Shandong,China Center of Bioinformatics School of Life Science and Technology,University of Electronic Science and Technology of China,Chengdu,China,Key Laboratory of Biophysics of Shandong Dezhou University,Dezhou,Shandong,China The College of Physics and Electronic Information of Dezhou University,Dezhou,Shandong,China Center of Bioinformatics School of Life Science and Technology,University of Electronic Science and Technology of China,Chengdu,China,Key Laboratory of Biophysics of Shandong Dezhou University,Dezhou,Shandong,China; The College of Physics and Electronic Information of Dezhou University,Dezhou,Shandong,China Center of Bioinformatics School of Life Science and Technology,University of Electronic Science and Technology of China,Chengdu,China

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This work was supported by grants from The National Natural Science Foundation of China (31000324, 61271378, 11447004), Natural Science Foundation of Shandong Province, China (ZR2012CL09, ZR2014AL014, ZR2014JL006) and the Taishan Scholar Program of Shandong

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    摘要:

    细胞穿膜肽(cell penetrating peptides,CPPs)是一种小分子多肽,能够容易地穿过细胞膜.这类分子,尤其是具有靶向功能的CPPs为高效率投送药物到靶细胞带来希望.因此,对其展开研究对于生物医学有着一定的意义.本工作主要从序列水平对具有不同穿膜活性的CPPs进行研究,试图找出影响CPPs穿膜活性的因素,以及不同活性CPPs与非穿膜肽(NonCPPs)序列上的差异,并引入一种分析生物序列的方法.我们基于CPPsite数据库和不同的文献获取CPPs和NonCPPs序列,并进一步从CPPs序列中提取具有高、中、低穿膜活性的穿膜肽(HCPPs、MCPPs、LCPPs)用于构建数据集.基于这些数据集,开展了以下研究:首先,利用方差分析的方法,对不同活性的CPPs以及NonCPPs的氨基酸及二级结构组成进行分析,发现氨基酸的静电与疏水相互作用对CPPs的穿膜活性起到了重要影响,同时螺旋结构和无规卷曲也会影响CPPs的穿膜活性;其次,使用理化性质与长度将不同活性的CPPs展示在二维平面上,发现在某些特殊的性质下不同活性的CPPs与NonCPPs可以产生聚簇现象,HCPPs、MCPPs以及LCPPs和NonCPPs被分成了三簇,这种现象显示了它们之间的差异;最后,本文引入了生物序列理化质心的概念,将组成序列的残基看作质点,进而把序列抽象成质点系进行研究,并将此方法应用到CPPs的分析中,通过PCA方法将不同活性的CPPs投射到三维平面上,结果发现绝大部分CPPs聚在一起,部分LCPPs与NonCPPs聚在一起.此工作对于CPPs的设计,以及理解不同活性CPPs序列上的差异具有一定的意义.另外,本文引入的生物序列理化质心的分析方法也可以用于其他生物问题的分析,同时它们可以作为某些生物分类问题的输入参数,在模式识别中起到一定的作用.

    Abstract:

    Cell penetrating peptides (CPPs) are kinds of small molecular peptides, which can penetrate cell membrane easily. Their discovery sheds light on delivering drugs into target efficiently. Therefore, the investigation of CPPs has crucial significance in biomedicine field. In this work we intended to find factors which have influence on CPPs penetrating activity and introduce a new method called physico-chemical mass center of bio-sequence. This method was enlightened by particle mechanics. We used it to analyze bio-sequence. In addition, the differences between all kinds of CPPs with different penetrating activities were also investigated. The CPPs and Non-cell penetrating peptides (NonCPPs) were obtained based on CPPsite database version 1.0 (http://crdd.osdd.net/raghava/cppsite1/) and references, respectively. After that we extracted CPPs with high, medium, and low penetrating activities (HCPPs, MCPPs, LCPPs), respectively. Firstly, the amino acids composition was calculated for every peptide in HCPPs, MCPPs, LCPPs datasets, individually. We used ANOVA to analyze the amino acids composition in HCPPs, MCPPs, LCPPs datasets. From the results we noticed that there has a significant difference for amino acids with electric charge and hydrophobic properties. These results revealed that electrostatic and hydrophobic interactions may play a key role in CPPs' penetrating activities. ANOVA analysis also revealed that helix and coil structure may also have influence on CPPs' activities. Secondly, CPPs and NonCPPs can yield a clustering phenomenon under some physicochemical features such as pK values, and their corresponding lengths. HCPPs, MCPPs, LCPPs, and NonCPPs can be divided into three groups. The differences between CPPs and NonCPPs can be reflected by the above phenomena. Lastly, as a case study we used the new concept named physico-chemical mass center of bio-sequence method encouraged by particle mechanics to study CPPs. The sequences can be represented by a series of points in the above method. Combining with principal component analysis (PCA), we found that the distribution of CPPs under their first, second and third scores can generate a cluster for CPPs. The differences between HCPPs, MCPPs, LCPPs and NonCPPs were also demonstrated by the above phenomenon. From this study, we can conclude that this work can help us to further understand the differences between them in terms of their primary structures and the factors affecting on their activities. Most important, the physico-chemical mass center can be used to analyze other biological issues as well as input features for biological pattern recognitions.

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曹赞霞,董川,赵立岭,王吉华.细胞穿膜肽的穿膜活性与序列特征的关系[J].生物化学与生物物理进展,2016,43(1):75-82

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  • 收稿日期:2015-09-01
  • 最后修改日期:2015-11-24
  • 接受日期:2015-12-01
  • 在线发布日期: 2016-01-19
  • 出版日期: 2016-01-20