Mimicking enzyme active sites in synthetic shape-programmable macromolecules to create enantioselective hydrogen-bond activated catalysts

美国国家科学基金会化学部的化学催化计划支持教授克里斯蒂安E。Schafmeister开发的分子，模仿生物酶的速率增强和精致的对映体，非对映体和区域选择性。 该小组已经开发出一种有效和系统的方法来合成预组织和高度功能化的大分子（“螺环低聚物”），可以创建类似于酶活性位点的形状可编程口袋。螺旋低聚物是由手性、官能化的双氨基酸通过酰胺键偶联而构建的立体化学丰富的梯形分子。Schafmeister小组与加州大学洛杉矶分校的Kenneth Houk教授及其小组合作，将理论酶设计与螺环聚合物合成方法学相结合，构建了新的催化剂。这些催化剂包括改进的、改性的脯氨酸羟醛催化剂、模拟丝氨酸酯酶并加速酯交换反应的三官能酰基转移催化剂、以及模拟酮类异构酶并加速Claisen重排和Diels-Alder反应的双官能氢键供体催化剂。 研究小组现在正在为这些反应开发更活跃的基于螺环低聚物的催化剂，方法是将反应基团组装在手性口袋内，通过共价锁定三个和四个螺环低聚物片段来创建预组织的大分子（2，000至5，000道尔顿）。 在这些口袋里，反应基团被组织起来以匹配过渡态模型。 口袋产生立体和区域选择性，通过形状互补与他们的基板。与酶不同，基于螺环低聚物的催化剂非常耐用;它们对变性免疫，并且在水或有机溶剂中以及在很宽的温度范围内发挥作用。这些催化剂是使用内部开发的软件CANDO设计的。 CANDO计划使用了Houk实验室与华盛顿大学的大卫贝克教授的实验室共同开发的改进的“由内而外”设计方法，以创建基于蛋白质的人工酶。一年级和二年级的本科生接受培训，使用CANDO计划设计自己的催化剂，因此，在完成实验室课程之前从事研究。 分子建模、过渡态理论和科学程序的技术在技术工作市场上很有价值。生物酶是催化剂，分子改变其他分子而不改变自己。 生物酶在环境温度和压力下操作，同时避免能量消耗和产生不需要的副产物，这些副产物损害了许多当前的人造催化剂。 天普大学的Christian Schafmeister教授和他的研究小组开发了系统的方法来研究酶样催化剂，这种催化剂具有高度的活性和选择性，同时比脆弱的生物酶更强大。该团队使用计算机辅助设计来预测催化位点，然后组装分子积木（分子乐高积木）来产生这些反应位点或口袋。 该集团通过将其催化剂构建成更大，更有选择性和更活跃的大分子来增强其催化剂的反应性。 鼓励本科生和研究生研究人员参与各级研究，从使用计算机程序设计自己的催化剂到在实验室生产催化剂，并测试分子的反应性和选择性。

The Chemical Catalysis Program of the NSF Division of Chemistry supports the efforts of Professor Christian E. Schafmeister of Temple University to develop molecules that mimic the rate enhancements and exquisite enantio-, diastereo-, and regioselectivity of biological enzymes. The group has developed an efficient and systematic approach to the synthesis of pre-organized and highly functionalized macromolecules ("spiroligomers") that can create shape-programmable pockets that resemble enzyme active sites. Spiroligomers are stereochemically rich ladder molecules constructed from chiral, functionalized bis-amino acids that are coupled through pairs of amide bonds. In collaboration with Professor Kenneth Houk and his group at the University of California, Los Angeles, the Schafmeister group combined theoretical enzyme design with spiroligomer synthetic methodology to construct new catalysts. These catalysts include an improved, modified proline aldol catalyst, a tri-functional acyl-transfer catalyst that mimics serine esterases and accelerates transesterification reactions, and a bifunctional hydrogen bond donating catalyst that mimics Ketosteroid Isomerase and accelerates Claisen rearrangements and Diels-Alder reactions. The research team is now developing more active spiroligomer-based catalysts for these reactions by assembling reactive groups within chiral pockets created by covalently locking three and four spiroligomer segments together to create pre-organized macromolecules (2,000 to 5,000 Daltons). Within these pockets, reactive groups are organized to match transition state models. The pockets engender stereo- and regioselectivity through shape complementary with their substrates. Unlike enzymes, spiroligomer-based catalysts are extremely robust; They are immune to denaturation and function in water or organic solvents and across a wide range of temperatures. These catalysts are designed using in-house developed software called CANDO. The CANDO program uses a modified "inside-out" design approach that the Houk laboratory developed together with the laboratory of Professor David Baker at the University of Washington to create artificial enzymes based on proteins. First and second year undergraduate students are trained to use the CANDO program to design their own catalysts and thus, are engaged in research prior to finishing their laboratory courses. The techniques of molecular modeling, transition state theory and scientific program are valuable in the technical job market.Biological enzymes are catalysts, molecules that alter other molecules without being changed themselves. Biological enzymes operate at ambient temperature and pressures while avoiding energy consumption and the generation of unwanted byproducts that impair many current man-made catalysts. Professor Christian Schafmeister and his group at Temple University develop systematic approaches towards enzyme-like catalysts that are highly active and selective while being much more robust than fragile biological enzymes. The team uses computer-aided design to predict catalytic sites and then assembles molecular building blocks (molecular Legos) to produce these reactive sites or pockets. The group enhances the reactivity of their catalysts by building them into larger, more selective and more active macromolecules. Undergraduate and graduate student researchers are encouraged to participate in all levels of the research from using computer programs to design their own catalysts to producing the catalyst in the laboratory and testing the molecules for reactivity and selectivity.