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两性离子多肽改善GLP-1生物活性的粗粒化分子模拟

滕家曼 刘玉婷 朱国梁 谌庄琳 陈彦涛

滕家曼, 刘玉婷, 朱国梁, 谌庄琳, 陈彦涛. 两性离子多肽改善GLP-1生物活性的粗粒化分子模拟[J]. 功能高分子学报, 2021, 34(3): 260-268. doi: 10.14133/j.cnki.1008-9357.20210118002
引用本文: 滕家曼, 刘玉婷, 朱国梁, 谌庄琳, 陈彦涛. 两性离子多肽改善GLP-1生物活性的粗粒化分子模拟[J]. 功能高分子学报, 2021, 34(3): 260-268. doi: 10.14133/j.cnki.1008-9357.20210118002
TENG Jiaman, LIU Yuting, ZHU Guoliang, SHEN Zhuanglin, CHEN Yantao. Coarse-Grained Molecular Simulation of Zwitterionic Polypeptides on Improving the Bioactivity of Glucagon-Like Peptide-1(GLP-1)[J]. Journal of Functional Polymers, 2021, 34(3): 260-268. doi: 10.14133/j.cnki.1008-9357.20210118002
Citation: TENG Jiaman, LIU Yuting, ZHU Guoliang, SHEN Zhuanglin, CHEN Yantao. Coarse-Grained Molecular Simulation of Zwitterionic Polypeptides on Improving the Bioactivity of Glucagon-Like Peptide-1(GLP-1)[J]. Journal of Functional Polymers, 2021, 34(3): 260-268. doi: 10.14133/j.cnki.1008-9357.20210118002

两性离子多肽改善GLP-1生物活性的粗粒化分子模拟

doi: 10.14133/j.cnki.1008-9357.20210118002
基金项目: 广东省自然科学基金(2018A0303130202);深圳市科技计划项目(JCYJ20170817100035677)
详细信息
    作者简介:

    滕家曼(1998—),女,硕士生,研究方向为生物大分子的分子模拟。E-mail:tengjiaman@foxmail.com

    陈彦涛,博士,任职于深圳大学化学与环境工程学院。长期从事生物医药材料的计算机模拟研究,近年来致力发展多尺度计算模型,并用于探讨药物蛋白控制释放的微观机理。主持完成多项国家自然科学基金及省市科技计划项目。被评为深圳市高层次专业人才(地方级)。以第一作者或通信作者在Acta BiomaterialiaInternational Journal of Biological MacromoleculesJournal of Physical Chemistry CLangmuir等学术期刊上发表SCI论文30余篇,以第一发明人授权中国发明专利1件。参与编著《高分子科学实验》及《自然科学经典文选导读》等高等院校教材

    通讯作者:

    陈彦涛,E-mail:ytchen@szu.edu.cn

  • 中图分类号: O617

Coarse-Grained Molecular Simulation of Zwitterionic Polypeptides on Improving the Bioactivity of Glucagon-Like Peptide-1(GLP-1)

  • 摘要: 以胰高血糖素样肽-1(GLP-1)与多肽的混合体系作为研究对象,利用粗粒化分子模拟对其作用模式进行研究。结果显示,3种混合体系都有利于GLP-1形成螺旋结构。其中,两性离子五肽VPKEG具有较强亲水性,在GLP-1周围形成疏松的保护层;而两性离子五肽VPREG与GLP-1形成较多静电作用;对照组五肽VPGAG具有较强疏水性,形成致密聚集体,未能给GLP-1提供足够保护。赖氨酸、谷氨酸组合让两性离子五肽VPKEG具备了恰当的亲疏水性和静电作用,既能维持GLP-1构象,也可避免被免疫蛋白识别,赋予其“隐身”特性。

     

  • 图  1  各模拟体系中GLP-1蛋白的二级结构随时间的变化情况

    Figure  1.  Time evaluation of the secondary structures for GLP-1 protein in different simulated systems

    图  2  各模拟体系中五肽的原子接触数(Atomic contact)随时间的变化情况:(a)五肽与水溶剂的接触数;(b)五肽与GLP-1蛋白的接触数

    Figure  2.  Time evaluation of the atomic contacts for pentapeptides with (a) water and (b) GLP-1 protein in different simulated systems

    图  3  热力学平衡后,各模拟体系中GLP-1蛋白的(a)二级结构分布及(b)末端距

    Figure  3.  (a) Distribution of secondary structures and (b) end-to-end distance of GLP-1 protein in different simulated systems when reaching thermodynamic equilibrium

    图  4  热力学平衡后,各模拟体系中GLP-1蛋白的典型构象

    Figure  4.  Typical conformation of GLP-1 protein in different simulated systems when reaching thermodynamic equilibrium

    图  5  (a)五肽在GLP-1周围的径向分布情况;(b)GLP-1各个残基与多肽的原子接触情况

    Figure  5.  (a) Radial distribution functions (RDF) of around GLP-1; (b) Atomic contacts with pentapeptides for each residue of GLP-1

    图  6  各模拟体系中多肽在GLP-1蛋白周围的典型分布

    Figure  6.  Typical distribution of pentapeptides around GLP-1 protein in different simulated systems

    图  7  各模拟体系中静电相互作用情况

    Figure  7.  The electrostatic interactions among GLP-1 protein and pentapeptides in different simulated systems

    图  8  各模拟体系中五肽各残基与GLP-1蛋白的原子接触数

    Figure  8.  Atomic contacts with GLP-1 for each residue of pentapeptide

    图  9  水分子在两性离子多肽特定残基周围的径向分布:(a)赖氨酸及精氨酸侧基N原子周围的水分子分布;(b)谷氨酸侧基O原子周围的水分子分布

    Figure  9.  Radial distribution of water molecules around some specific residues of zwitterionic pentapeptides: (a) The distribution of water molecules around N atoms of the side groups of LYS and ARG; (b) The distribution of water molecules around the O atom of the side groups of GLU

    图  10  各模拟体系中GLP-1蛋白的动力学性质:(a)各残基的根均方(RMSF)涨落情况;(b)GLP-1均方位移(MSD)随时间变化情况

    Figure  10.  Kinetic properties of GLP-1 protein in different simulated systems: (a) The root-mean-squared fluctuation (RMSF) of each residue;(b) The mean-squared displacement (MSD) of GLP-1 as functions time

  • [1] ZELIKIN A N, EHRHARDT C, HEALY A M. Materials and methods for delivery of biological drugs [J]. Nat Chem,2016,8(11):997-1007. doi: 10.1038/nchem.2629
    [2] KO J H, MAYNARD H D. A guide to maximizing the therapeutic potential of protein-polymer conjugates by rational design [J]. Chem Soc Rev,2018,47(24):8998-9014. doi: 10.1039/C8CS00606G
    [3] HARRIS J M, CHESS R B. Effect of pegylation on pharmaceuticals [J]. Nat Rev Drug Discov,2003,2(3):214-221. doi: 10.1038/nrd1033
    [4] ZAMAN R, ISLAM R A, IBNAT N, et al. Current strategies in extending half-lives of therapeutic proteins [J]. J Control Release,2019,301:176-189. doi: 10.1016/j.jconrel.2019.02.016
    [5] ZHANG P, SUN F, LIU S, et al. Anti-PEG antibodies in the clinic: Current issues and beyond PEGylation [J]. J Control Release,2016,244:184-193. doi: 10.1016/j.jconrel.2016.06.040
    [6] QI Y, CHILKOTI A. Protein-polymer conjugation-moving beyond PEGylation [J]. Curr Opin Chem Biol,2015,28:181-193. doi: 10.1016/j.cbpa.2015.08.009
    [7] 张冲, 吕华. 蛋白质-聚氨基酸偶联物的高效合成与应用 [J]. 高分子学报,2018(1):21-31. doi: 10.11777/j.issn1000-3304.2018.17204

    ZHANG C, LYU H. Efficient synthesis and application of protein-poly(α-amino acid) conjugates [J]. Acta Polymerica Sinica,2018(1):21-31. doi: 10.11777/j.issn1000-3304.2018.17204
    [8] 闫树鹏, 张冲, 吕华. 两性离子聚合物的研究进展 [J]. 功能高分子学报,2020,33(4):1-14.

    YAN S P, ZHANG C, LYU H. Advances in zwitterionic polymers [J]. Journal of Functional Polymers,2020,33(4):1-14.
    [9] WHITE A D, NOWINSKI A K, HUANG W J, et al. Decoding nonspecific interactions from nature [J]. Chem Sci,2012,3(12):3488-3494. doi: 10.1039/c2sc21135a
    [10] KEEFE A J, CALDWELL K B, NOWINSKI A K, et al. Screening nonspecific interactions of peptides without background interference [J]. Biomaterials,2013,34(8):1871-1877. doi: 10.1016/j.biomaterials.2012.11.014
    [11] LIU E J, SINCLAIR A, KEEFE A J, et al. EKylation: Addition of an alternating-charge peptide stabilizes proteins [J]. Biomacromolecules,2015,16(10):3357-3361. doi: 10.1021/acs.biomac.5b01031
    [12] LIU E J, JIANG S. Expressing a monomeric organophosphate hydrolase as an EK fusion protein [J]. Bioconjug Chem,2018,29(11):3686-3690. doi: 10.1021/acs.bioconjchem.8b00607
    [13] BANSKOTA S, YOUSEFPOUR P, KIRMANI N, et al. Long circulating genetically encoded intrinsically disordered zwitterionic polypeptides for drug delivery [J]. Biomaterials,2019,192:475-485. doi: 10.1016/j.biomaterials.2018.11.012
    [14] SHAO Q, HE Y, WHITE A D, et al. Different effects of zwitterion and ethylene glycol on proteins [J]. J Chem Phys,2012,136(22):225101.
    [15] SETTANNI G, ZHOU J, SUO T, et al. Protein corona composition of poly(ethylene glycol)- and poly(phosphoester)-coated nanoparticles correlates strongly with the amino acid composition of the protein surface [J]. Nanoscale,2017,9(6):2138-2144. doi: 10.1039/C6NR07022A
    [16] GODDARD T D, HUANG C C, MENG E C, et al. UCSF ChimeraX: Meeting modern challenges in visualization and analysis [J]. Protein Sci,2018,27(1):14-25. doi: 10.1002/pro.3235
    [17] HAN W, WAN C K, JIANG F, et al. PACE force field for protein simulations. 1. Full parameterization of version 1 and verification [J]. J Chem Theory Comput,2010,6(11):3373-3389. doi: 10.1021/ct1003127
    [18] HAN W, WAN C K, WU Y D. PACE force field for protein simulations. 2. Folding simulations of peptides [J]. J Chem Theory Comput,2010,6(11):3390-3402. doi: 10.1021/ct100313a
    [19] XIONG Q, JIANG Y, CAI X, et al. Conformation dependence of diphenylalanine self-assembly structures and dynamics: Insights from hybrid-resolution simulations [J]. ACS Nano,2019,13(4):4455-4468. doi: 10.1021/acsnano.8b09741
    [20] ABRAHAM M J, MURTOLA T, SCHULZ R, et al. GROMACS: High performance molecular simulations through multi-level parallelism from laptops to supercomputers [J]. SoftwareX,2015,1-2:19-25. doi: 10.1016/j.softx.2015.06.001
    [21] HUMPHREY W, DALKE A, SCHULTEN K. VMD: Visual molecular dynamics[J]. Journal of Molecular Graphics, 1996, 14 (1): 33 (8), 27-28.
    [22] DELANO W L. The PyMOL Molecular Graphics System; DeLano Scientific: San Carlos, CA, USA, 2002.
    [23] MANANDHAR B, AHN J M. Glucagon-like peptide-1 (GLP-1) analogs: Recent advances, new possibilities, and therapeutic implications [J]. J Med Chem,2015,58(3):1020-1037. doi: 10.1021/jm500810s
    [24] UNDERWOOD C R, GARIBAY P, KNUDSEN L B, et al. Crystal structure of glucagon-like peptide-1 in complex with the extracellular domain of the glucagon-like peptide-1 receptor [J]. J Biol Chem,2010,285(1):723-730. doi: 10.1074/jbc.M109.033829
    [25] THORNTON K, GORENSTEIN D G. Structure of glucagon-like peptide (7-36) amide in a dodecylphosphocholine micelle as determined by 2D NMR [J]. Biochemistry,1994,33(12):3532-3539. doi: 10.1021/bi00178a009
    [26] CHANG X, KELLER D, BJØRN S, et al. Structure and folding of glucagon-like peptide-1-(7-36)-amide in aqueous trifluoroethanol studied by NMR spectroscopy [J]. Magnetic Resonance in Chemistry,2001,39(8):477-483. doi: 10.1002/mrc.880
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出版历程
  • 收稿日期:  2021-01-18
  • 刊出日期:  2021-06-01

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