蛋白质顺磁标记中探针的设计、合成与表征
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摘要
X-射线晶体衍射和核磁共振是研究生物大分子三维结构的两种主要技术手段,与X-射线晶体衍射相比,核磁共振在某些方面具有明显的优势,比如：样品不需要结晶,可以在接近生理条件下进行探测,可以用来研究生物大分子在溶液中的空间结构和功能的关系及生物样品中的动态行为等等。传统核磁共振主要用NOE (Nuclear Overhauser Effect)及二面角作为结构限制条件,然而,在研究蛋白质-蛋白质,蛋白质-配体相互作用时,一般情况下获得分子间NOE较为繁琐；另外,在研究多结构域的生物大分子的结构时,由于传统核磁共振只能提供短程的结构限制,很难获得结构域之间的结构信息,传统核磁共振在解决以上问题时遇到较大的挑战。
与传统的核磁共振相比,顺磁核磁共振能够提供长程的结构限制,在分析大蛋白的溶液构象变化,蛋白质-蛋白质或配体相互作用等方面具有明显的优势。通常情况下蛋白质不含顺磁中心,要获得顺磁性结构信息需要对蛋白质进行顺磁标记,为解决目前国际上在蛋白质顺磁标记方面面临的问题譬如二硫键的不稳定性、标签的体积与刚性,本人设计合成了一系列新型的顺磁探针并进行了蛋白质的修饰,另外还探讨了巯基和碳碳双键的Michael加成反应的动力学。
本文主要研究内容如下：设计合成了一系列的含双功能团的顺磁标签,通过合理的路线,以较高的收率合成一系列含有活化的碳碳双键(Michael受体)的顺磁标签；通过紫外可见分光光度计研究了顺磁标签L1和L2和L-半胱氨酸的反应动力学。结果发现,L1在中性水溶液中,不需要任何自由基引发剂的情况下,和L-半胱氨酸反应良好,并且L1具有明显的巯基选择性,和赖氨酸、甲硫氨酸等含官能团的氨基酸均不反应。L2与L1相似,但是L2与L-半胱氨酸的反应慢,这为根据巯基活性不同选择性标记含有多自由巯基的蛋白质提供了可能；针对二硫键容易发生置换及在高pH和还原环境下不稳定的问题,本实验首次利用麦克尔加成的方式把顺磁标签连接到蛋白质上,巯基麦克尔加成形成稳定的巯醚键,与二硫键相比,巯醚键在高pH及还原性环境下均能稳定存在。实验发现,L1和Ubiquitin-T22C或ArgN连接以后,滴加顺磁金属离子,均获得高质量的顺磁图谱；针对L1配位数少的问题,设计合成了L2顺磁标签,和L1相比,L2和镧系金属离子的络合能力更强,L2和Ubiquitin-G47C连接以后,滴加顺磁金属,大部分氨基酸残基有明显的赝接触化学位移。
X-ray crystallography and nuclear magnetic resonance(NMR) are the mostly used techniques in obtaining the three-dimensional structure of biological macromolecules with atom resolution, Compared with X-ray crystallography, NMR has advantages in:(1) the proteins is not ncecessarily crystallized;(2) the measurement condition is close to physiological environment;(3) NMR is able to investigate the dynamic properties of biomolecues in solution. NOEs and dihedral angles are the main structural constraints in structural biology by virtue of NMR. intermolecular NOEs are difficult to assign in many protein-protein and tranditional NMR becomes awkard in study of domain displayment in multiple-domain proteins.
Site-specific labeling of proteins with paramagnetic ions especially lanthanides greatly enhances the power of NMR in structural biology. The dipolar interactions between unpaired electrons and nuclei spins of protein provide a rich source of structural information of proteins. At present, chemically synthesized tags are almost invariably attached to the protein by formation of one or two disulfide bonds. In this study, we report a new method of site-specific tagging proteins with paramagnetic molecules vis Michael addition reaction. We first designed and synthesized a series of new paramagnetic tags which contain difunctional groups, and investigated the kinetics of the reaction between paramagnetic tags(Ll, L2) and L-Cysteine. We show that L1and L2are ideals paramagnetic tag in labeling of proteins. And significant pseudocontact shift(PCS) were observed in the L1/L2derivatized protein adducts. In summary, we show that thiol-ene like Michael addition reaction is a valuable approach in site-specific labeling of proteins with chemically inert paramagnetic tags.
与传统的核磁共振相比,顺磁核磁共振能够提供长程的结构限制,在分析大蛋白的溶液构象变化,蛋白质-蛋白质或配体相互作用等方面具有明显的优势。通常情况下蛋白质不含顺磁中心,要获得顺磁性结构信息需要对蛋白质进行顺磁标记,为解决目前国际上在蛋白质顺磁标记方面面临的问题譬如二硫键的不稳定性、标签的体积与刚性,本人设计合成了一系列新型的顺磁探针并进行了蛋白质的修饰,另外还探讨了巯基和碳碳双键的Michael加成反应的动力学。
本文主要研究内容如下：设计合成了一系列的含双功能团的顺磁标签,通过合理的路线,以较高的收率合成一系列含有活化的碳碳双键(Michael受体)的顺磁标签；通过紫外可见分光光度计研究了顺磁标签L1和L2和L-半胱氨酸的反应动力学。结果发现,L1在中性水溶液中,不需要任何自由基引发剂的情况下,和L-半胱氨酸反应良好,并且L1具有明显的巯基选择性,和赖氨酸、甲硫氨酸等含官能团的氨基酸均不反应。L2与L1相似,但是L2与L-半胱氨酸的反应慢,这为根据巯基活性不同选择性标记含有多自由巯基的蛋白质提供了可能；针对二硫键容易发生置换及在高pH和还原环境下不稳定的问题,本实验首次利用麦克尔加成的方式把顺磁标签连接到蛋白质上,巯基麦克尔加成形成稳定的巯醚键,与二硫键相比,巯醚键在高pH及还原性环境下均能稳定存在。实验发现,L1和Ubiquitin-T22C或ArgN连接以后,滴加顺磁金属离子,均获得高质量的顺磁图谱；针对L1配位数少的问题,设计合成了L2顺磁标签,和L1相比,L2和镧系金属离子的络合能力更强,L2和Ubiquitin-G47C连接以后,滴加顺磁金属,大部分氨基酸残基有明显的赝接触化学位移。
X-ray crystallography and nuclear magnetic resonance(NMR) are the mostly used techniques in obtaining the three-dimensional structure of biological macromolecules with atom resolution, Compared with X-ray crystallography, NMR has advantages in:(1) the proteins is not ncecessarily crystallized;(2) the measurement condition is close to physiological environment;(3) NMR is able to investigate the dynamic properties of biomolecues in solution. NOEs and dihedral angles are the main structural constraints in structural biology by virtue of NMR. intermolecular NOEs are difficult to assign in many protein-protein and tranditional NMR becomes awkard in study of domain displayment in multiple-domain proteins.
Site-specific labeling of proteins with paramagnetic ions especially lanthanides greatly enhances the power of NMR in structural biology. The dipolar interactions between unpaired electrons and nuclei spins of protein provide a rich source of structural information of proteins. At present, chemically synthesized tags are almost invariably attached to the protein by formation of one or two disulfide bonds. In this study, we report a new method of site-specific tagging proteins with paramagnetic molecules vis Michael addition reaction. We first designed and synthesized a series of new paramagnetic tags which contain difunctional groups, and investigated the kinetics of the reaction between paramagnetic tags(Ll, L2) and L-Cysteine. We show that L1and L2are ideals paramagnetic tag in labeling of proteins. And significant pseudocontact shift(PCS) were observed in the L1/L2derivatized protein adducts. In summary, we show that thiol-ene like Michael addition reaction is a valuable approach in site-specific labeling of proteins with chemically inert paramagnetic tags.
引文
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