International Research Fellowship Program: Preparation of a Polypeptide-Based Dendrimer Library for the Development and Design of Artificial Enzymes

[401973liang]国际研究奖学金计划使美国科学家和工程师能够在国外进行3至24个月的研究。该计划的奖励为联合研究提供了机会，并利用独特或互补的设施、专业知识和国外的实验条件。该奖项将支持Catherine O. Liang博士与瑞士伯尔尼大学Jean-Louis Reymond博士进行为期22个月的研究。鉴于自然发生系统的复杂性和复杂性，合理的酶设计是一项具有挑战性和艰巨的任务。目前的技术还没有开发出一种方法来设计氨基酸序列，使其可预测地折叠成所需的构象，从而产生具有特定功能的分子。科学家们不得不转向通过诸如位点定向诱变和活性位点化学修饰等技术来修饰天然存在的酶框架。为了应对开发大型，复杂的三维酶模拟物的挑战，新的基于肽的树状大分子文库正在研究中。树状大分子是高度分支、控制良好、单分散的大分子，具有类似于天然酶的球状形态。它们特有的分支和明确的内部结构提供了一种“预折叠”的结构，可以模仿基于肽的生物分子。目标结构的制备是通过固相肽合成进行的。与许多专注于单一目标的方法不同，多样性问题是通过组合策略来解决的，以产生大量不同的图书馆成员。一种互补的方法侧重于目标文库的制备，例如催化三联体凝乳胰蛋白酶- His， Asp, Ser -。枝状大分子的分支结构和氨基酸重复单元的结合为仿生应用开辟了可能性。通过鉴定底物选择性大分子来筛选树状大分子在传感或“人工鼻子”过程中的活性。此外，氨基酸残基创造的独特纳米环境对催化活性进行了评估。催化碳-碳键形成反应的潜在醛缩酶和酯酶模拟物在染料标记底物的荧光测定中被筛选。显然，探索以肽为基础的树状大分子的许多可能性尚未被发现。

0401973LiangThe International Research Fellowship Program enables U.S. scientists and engineers to conduct three to twenty-four months of research abroad. The program's awards provide opportunities for joint research, and the use of unique or complementary facilities, expertise and experimental conditions abroad.This award will support a twenty-two-month research fellowship by Dr. Catherine O. Liang to work with Dr. Jean-Louis Reymond at University of Berne in Switzerland.In light of the complexity and sophistication of naturally occurring systems, rational enzyme design is a challenging and daunting task. Current technology has not yet developed a way to design an amino acid sequence that folds predictably into a desired conformation resulting in a molecule capable of a specific function. Scientists have had to turn to modification of naturally occurring enzyme frameworks through techniques such as site-directed mutagenesis and chemical modification of the active site. In response to the challenges of developing a large, sophisticated, 3-dimensional enzyme mimic, novel peptide-based dendrimer libraries are being investigated. Dendrimers are highly branched, well-controlled, monodisperse macromolecules and offer a globular morphology similar to naturally occurring enzymes. Their characteristic branching and well-defined interior provides a 'pre-folded' architecture amenable to the mimicry of peptide-based biomolecules. Preparation of target structures is carried out through solid-phase peptide synthesis. Unlike many approaches that focus on a singular target, the issue of diversity is addressed through a combinatorial strategy to generate multitudes of different library members. A complementary approach focusing on the preparation of targeted libraries like the catalytic triad chymotrypsin - His, Asp, Ser - for instance, is included. The combination of the branched, hierarchical structure of dendrimers and amino acid repeat units opens up possibilities towards biomimetic applications. Dendrimers are screened for activity in sensing or "artificial nose" processes through identification of substrate selective macromolecules. In addition, the unique nanoenvironment created by the amino-acid residues is evaluated for catalytic activity. Potential aldolase, which catalyze carbon-carbon bond forming reactions, and esterase mimics are screened in fluorogenic assays with dye-labeled substrates. Clearly many possibilities of exploration into peptide-based dendrimers have yet to be uncovered.