Catalytic methods for site-specific modification of natural proteins

通过这个奖项，化学部门的生命过程化学项目资助莱斯大学的Zachary Ball博士研究蛋白质修饰的化学反应。蛋白质是非常大而复杂的分子，选择改变蛋白质仍然是一个艰巨的挑战。尽管如此，化学修饰的蛋白质代表着诱人的机会。修饰蛋白的应用包括用于涂层或绿色能源的生物材料和用于理解、干扰和抑制生物途径的生物探针。该奖项的重点是开发新的金属介导的蛋白质修饰方法。这些新方法允许制备具有新结构、反应性和生物特性的新位点。该研究项目为本科生、研究生和博士后提供有机合成和无机合成化学方面的培训。此外，这些研究参与者正在接受蛋白质化学技术和现代分析方法方面的培训。一项综合推广计划正在向当地高中教师和学生介绍现代蛋白质化学和分析方法。为了开发序列选择性蛋白质修饰催化剂，本项目采用铑（II）偶联物，可以在分子识别的基础上修饰蛋白质，无论是纯化的还是裂解的。催化修饰为配体结合的存在和位置提供了共价读数，从而可以识别“命中”化合物的配体结合位点。反应性还可以用来量化现有方法难以研究的弱、瞬态相互作用的抑制剂。在新的方向上，硼酸盐试剂的Chan-Lam偶联允许铜催化修饰肽和蛋白质，具有独特的序列特异性。金属酶活性位点的非自然化学修饰已成为金属酶设计的有力工具。硼酸偶联有望为构建具有新功能和反应性的杂交金属蛋白提供令人兴奋的新工具。

With this award, the Chemistry of Life Processes Program in the Chemistry Division is funding Dr. Zachary Ball from Rice University to investigate chemical reactions for protein modification. Proteins are incredibly large and complex molecules and selective alteration of proteins remains a daunting challenge. Nonetheless, chemically-modified proteins represent tantalizing opportunities. Applications of modified proteins include biomaterials for coatings or green energy and biological probes to understand, perturb, and inhibit biological pathways. Efforts under this award focus on developing new metal-mediated methods for protein modification. These novel methods allow the preparation of new sites with novel structures, reactivity, and biological properties. The research project is providing undergraduate students, graduate students, and postdoctoral fellows with training in synthetic organic and inorganic chemistry. In addition, these research participants are receiving training in techniques and modern analytical methods of protein chemistry. An integrated outreach program is introducing modern protein chemistry and analytical methods to local high school teachers and their students.In order to develop sequence-selective protein modification catalysts, this project employs rhodium(II) conjugates that enable modification of proteins, whether purified or in lysate, on the basis of molecular recognition. Catalytic modification provides a covalent readout for the presence and location of ligand binding, and thus allows identification of ligand-binding sites of "hit" compounds. The reactivity can also be harnessed to quantify inhibitors of weak, transient interactions that are difficult to study with existing methods. In a new direction, Chan-Lam coupling of boronate reagents allows copper-catalyzed modification of peptides and proteins, with unique sequence specificity. Unnatural chemical modification of metalloenzyme active sites has emerged as a powerful tool in metalloenzyme design. Boronate coupling promises to provide exciting new tools to build hybrid metalloproteins with new function and reactivity.