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化学进展 2020, Vol. 32 Issue (6): 687-697 DOI: 10.7536/PC191020   后一篇

• 综述与评论 •

DNA-多肽复合分子的设计、组装与应用

王子瑄1, 王跃飞1,2,**(), 齐崴1,2,3, 苏荣欣1,2,3, 何志敏1   

  1. 1. 天津大学化工学院 天津 300072
    2. 天津大学化学工程联合国家重点实验室 天津 300072
    3. 天津化学化工协同创新中心 天津 300072
  • 收稿日期:2019-10-29 修回日期:2020-01-19 出版日期:2020-06-05 发布日期:2020-04-13
  • 通讯作者: 王跃飞
  • 作者简介:
    ** Corresponding author e-mail:
  • 基金资助:
    国家自然科学基金项目(21606166, 21621004, 51773149)

Design, Self-Assembly and Application of DNA-Peptide Hybrid Molecules

Zixuan Wang1, Yuefei Wang1,2,**(), Wei Qi1,2,3, Rongxin Su1,2,3, Zhimin He1   

  1. 1. School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, China
    2. State Key Laboratory of Chemical Engineering, Tianjin University, Tianjin 300072, China
    3. Collaborative Innovation Center of Chemical Science and Engineering(Tianjin), Tianjin 300072, China;
  • Received:2019-10-29 Revised:2020-01-19 Online:2020-06-05 Published:2020-04-13
  • Contact: Yuefei Wang
  • Supported by:
    the National Natural Science Foundation of China(21606166, 21621004, 51773149)

DNA-多肽复合分子作为一类新型的自组装分子受到研究人员的广泛关注。DNA分子具有可编程性、高特异性、功能多样等优点,多肽分子是一类重要的生物小分子,能够通过分子自组装形成具有不同结构的纳米材料,因此,将二者通过共价交联,可以获得具有多级自组装行为的DNA-多肽复合分子,能够实现两类重要生物分子功能的集成优化,合成具有不同结构与功能的超分子自组装材料。此外,通过酶催化、DNA杂化、DNA链置换反应等,还可实现对多肽-DNA复合分子自组装行为的动态调控,进而模拟生命系统中复杂动态的自组装结构,强化相关材料在生物、化学、材料等领域的应用。本文讨论了DNA-多肽复合分子的设计、组装与应用方面的最新进展,最后基于目前DNA-多肽复合分子存在的一些问题对DNA-多肽复合分子的研究做了展望。

As a new kind of self-assembled molecules, DNA-peptide hybrid molecules have attracted great interests. DNA has the advantages of programmability, high specificity and versatility. Peptides are a kind of important biological small molecules, which can form nanomaterials with various structures through molecular self-assembly. Therefore, DNA and peptide can be cross-linked with each other to form DNA-peptide hybrid molecules with hierarchical self-assembly behavior. In this way, the integration of the functions of two important biomolecules can be realized, and the supramolecular materials with different structures and functions can be assembled. Moreover, through the combination of enzyme catalysis, DNA hybridization, and strand displacement reactions, we are able to control the dynamic self-assembly of the peptide-DNA conjugates. This allows us to mimic the complex dynamic structures existing in biological systems, which will have great potential applications in biology, chemistry and materials science. In this paper, the latest progress in the design, self-assembly and applications of DNA-polypeptide hybrid molecules are reviewed. Some problems with regard to DNA-polypeptide molecules are summarized, and the prospect of the research on DNA-polypeptide molecules is made.

Contents

1 Introduction
2 Design of DNA-peptide hybrid molecules
3 Assembly and regulation of DNA-peptide hybrid molecules

3.1 Self-assembly mechanism

3.2 Supramolecular self-assembly of DNA-polypeptide hybrid molecules

3.3 Dynamic self-assembly of DNA-amphiphilic peptide molecules

4 Applications of functional materials assembled by DNA-peptide hybrid molecules

4.1 Biomedical applications

4.2 3D bioprinting

5 Conclusion and outlook
()
表1 DNA-多肽复合分子的设计、组装与应用
Table 1 Design, self-assembly and application of DNA-peptide hybrid molecules
图1 (a)DNA与短肽复合分子以及DNA与聚合物多肽复合分子的结构示意图;(b)两种将功能基团引入DNA-多肽复合分子的方法;(c)PPLG-g-DNA 分子刷的合成路线[35];(d)用双功能交联剂合成DNA-肽复合物[43];(e)环辛炔修饰的寡核苷酸与叠氮基-赖氨酸封端的两亲性多肽之间的交联反应[36];(f)利用配体-金属电荷转移将功能肽与DNA分子结构[42]
Fig. 1 (a) DNA-short peptide hybrid molecule and DNA-polypeptide hybrid molecule; (b) Two methods of introducing functional groups into DNA-peptide molecules; (c) Synthetic routes of PPLG-g-DNA molecular brush[35]; (d) Synthesis of DNA-peptide conjugates using a bifunctional cross-linker[43]; (e) Crosslinking reaction between cyclooctyne modified oligonucleotide and azido-lysine-terminated PA.[36]; (f) Direct incorporation of functional peptides with M-DNA through ligand-to-metal charge transfer[42]
图2 (a,b)多肽α-螺旋与β-折叠片二级结构[54];(c)两亲性多肽自组装示意图[54];(d)DNA链置换反应示意图及其位移动力学[53]
Fig. 2 (a,b) Schematic diagram of the α-helix and β-sheet secondary structures of the peptides[54]; (c) Schematic illustration showing the self-assembly of amphiphilic peptides[54]; (d) Schematic diagram of the DNA chain displacement reaction and its dynamics[53]
图3 (a)具有多修饰位点的多肽-DNA水凝胶的形成机理;(b)水凝胶自愈合示意图;(c)水凝胶的可注射性;(d)聚(γ-丙炔基-L-谷氨酸)与叠氮化物-DNA反应制备分子刷,再分别和ds-DNA、DNA交联剂交联[35]
Fig. 3 (a) The formation mechanism of the polypeptide-DNA hydrogel with rationally designed multi-modification sites; (b) The schematic mechanism of the self-healing and fusion behaviors of the DNA-peptide hydrogels; (c) Injectability of the hydrogels; (d) γ-propargyl-L-glutamate N-carboxyanhydride(PLG-NCA) reacts with azide-functionalized DNA strands to synthesize molecular brushes, which are then crosslinked with ds-DNA and DNA crosslinker, respectively[35]
图4 (a)DNA-PA复合分子与PA共组装成纳米纤维;(b)PA分子与PA-DNA复合分子示意图;(c)两根由DNA-两亲性多肽自组装形成的纳米纤维通过表面互补DNA链的杂化反应进行交联;(d)纤维束生长速率是纤维内(E intra)和纤维间能量(E inter)的函数;(e)可逆凝胶的扫描电镜显微照片,比例尺:10 μm[18]
Fig. 4 (a) Schematic diagram of PA molecule and PA-DNA molecule; (b) Nanofibers formed by co-assembly of PA with DNA-PA molecules; (c) Illustration of peptide amphiphile fibers cross-linked by DNA hybridization; fibers are shown in their initial state prior to monomer exchange; (d) Bundle growth rate as a function of intra- and interfiber energies(E intra, E inter); (e) SEM images showing the reversible fiber structures during heating-cooling cycle or by addition of DNA invader and anti-invader, scale: 10 μm[18]
图5 (a)多肽-DNA复合纤维之间通过DNA链之间的杂化反应进行交联,形成纤维束结构;(b)纤维束结构的TEM图像;(c)升高温度之后,多肽-DNA纤维束解聚为互相独立的单根纳米纤维的TEM图像;(d)通过DNA链置换反应,诱导多肽-DNA纤维束解聚为互相独立的单根纳米纤维的TEM图像;e)在提高pH前后与添加DNA消化酶前后多肽-DNA分子及其组装体结构的TEM照片[38]
Fig. 5 (a) Schematic of fiber bundling with DNA handles; (b) TEM image of the annealed complementary assembly; (c) Schematic and TEM image of the heated complementary pepDNA assembly; (d) TEM image and schematic of the strand displacement reaction products; (e) Molecular graphics representation and corresponding morphologies observed by TEM of pep-DNA before and after raising the pH or adding DNase to digest the DNA block[38]
图6 (a)核肽的聚集状态可通过酶催化ATP与ADP的转化进行可逆控制;(b)利用一对反作用酶相互转化ATP与ADP来控制核酸肽的自组装;(c)与Alexa ATP和核酸肽-NBD(50 mm)孵育的SA/DX5细胞的CLSM图像(比例尺: 5 mm)[39]
Fig. 6 (a) Interaction of assemblies of nucleopeptide with ATP or ADP and the reversible phase transition of the assemblies controlled by a pair of counteracting enzymes; (b) Employ a pair of counteracting enzymes to interconvert ATP and ADP for controlling the self-assembly of nucleopeptide; (c) CLSM images of the MES-SA/dx5 cells incubated with Alexa-ATP and NP1-NBD(50 mm). Scale bar: 5 mm[39]
图7 (a,b)单根纳米纤维与成束纳米纤维之间的转化;(c)激光共聚焦显微镜图像显示动态结构变化(从单个纤维到束状纤维再到单个纤维)对皮质星形胶质细胞性质的影响(从左到右),GFAP(绿色),细胞核(DAPI,蓝色),比例尺: 50 μm[18]
Fig. 7 (a, b) Conversion between individual nanofibers and nanofiber bundles; (c) Confocal microscopy images of astrocytes plated on individual fibers(left), on bundled fibers(center), and after switching from bundles to individual fibers(right). Staining for GFAP(green) and cell nuclei(DAPI, blue) reveals cells with na?ve morphology on substrates of individual fibers and reactive morphology on substrates of bundled fibers. Scale bar: 50 μm[18]
图8 (a)适配体和两亲性肽共组装物成纳米纤维;(b)根据自由适配体和apt-PAN系统的不同DNA浓度的过程曲线计算的初始降解速度的双倒数图[36]
Fig. 8 (a) Molecular representation of the coassembly of aptamer and diluent peptide amphiphiles; (b) Double-reciprocal plot of the initial degradation velocity calculated from the progress curves for various DNA concentrations for the free aptamer and apt-PAN systems[36]
图9 将多肽-DNA水凝胶3D打印成具有不同层次的结构:(a)一维点阵;(b)二维字母;(c)三维形状;(d)表明三维打印体具有一定的机械强度[40]
Fig. 9 3D printing of polypeptide-DNA hydrogel into 3D structures with blue dye added for visualization: (a) an array of printed droplets with an increasing gradient of layers. Inset, a lifted hydorgel with 20 layers; (b) the letters “THU” printed with 5 layers; (c) a triangle printed with 10 layers; (d) shows that the printed hydrogel structure is strong enough to be picked up with tweezers[40]
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