An Enzyme Model Which Mimics Chymotrypsin and N‑Terminal Hydrolases

Enzymes are the most efficient and specific catalysts to date. Although they have been thoroughly studied for years, building a true enzyme mimic remains a challenging and necessary task. Here, we show how a three-dimensional geometry analysis of the key catalytic residues in natural hydrolases has been exploited to design and synthesize small-molecule artificial enzymes which mimic the active centers of chymotrypsin and N-terminal hydrolases. The optimized prototype catalyzes the methanolysis of the acyl enzyme mimic with a half-life of only 3.7 min at 20 °C, and it is also able to perform the transesterification of vinyl acetate at room temperature. DFT studies and X-ray diffraction analysis of the catalyst bound to a transition state analogue proves the similarity with the geometry of natural hydrolases.酶是迄今为止效率最高、特异性最强的催化剂。尽管经过多年深入研究，构建真正的酶模拟物仍是一项兼具挑战性与必要性的任务。本研究通过对天然水解酶的关键催化残基开展三维几何结构分析，成功设计并合成了能够模拟胰凝乳蛋白酶与N端水解酶活性中心的小分子人工酶。经优化后的原型催化剂在20℃条件下可催化酰基酶模拟物的甲醇解反应，半衰期仅为3.7分钟；同时该催化剂还能在室温下完成乙酸乙烯酯的酯交换反应。针对结合过渡态类似物的催化剂开展的密度泛函理论（DFT）研究与X射线衍射分析，证实了该催化剂与天然水解酶的几何结构具有高度相似性。