Transition Path Sampling Study of Engineered Enzymes That Catalyze the Morita-Baylis-Hillman Reaction: Why Is Enzyme Design so Difficult?
Transition Path Sampling Study of Engineered Enzymes That Catalyze the Morita-Baylis-Hillman Reaction: Why Is Enzyme Design so Difficult?
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DOI：
10.1021/acs.jcim.4c00045
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发表时间：
2024-03-07
影响因子：
5.6
通讯作者：
Schwartz，Steven
中科院分区：
文献类型：
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作者：
Balasubramani，Sree Ganesh;Korchagina，Kseniia;Schwartz，Steven
人们希望在实验室中设计的人工酶可以有效地替代用于合成有机分子的化学催化剂。然而，人工酶的设计是具有挑战性的，需要详细的分子水平分析，以了解它们促进的机制，以便设计有效的变体。在这项研究中，我们通过计算研究熟练的Morita-Baylis-Hillman酶的机制，使用计算设计和定向进化的组合。强大的过渡路径采样方法与深入的后处理分析相结合，已成功用于阐明这种实验室优化的酶催化反应的不同化学途径、过渡态、蛋白质动力学和自由能垒。这项研究解释了酶中不同的化学修饰如何以静态设计算法无法预测的方式影响其催化活性。
It is hoped that artificial enzymes designed in laboratories can be efficient alternatives to chemical catalysts that have been used to synthesize organic molecules. However, the design of artificial enzymes is challenging and requires a detailed molecular-level analysis to understand the mechanism they promote in order to design efficient variants. In this study, we computationally investigate the mechanism of proficient Morita–Baylis–Hillman enzymes developed using a combination of computational design and directed evolution. The powerful transition path sampling method coupled with in-depth post-processing analysis has been successfully used to elucidate the different chemical pathways, transition states, protein dynamics, and free energy barriers of reactions catalyzed by such laboratory-optimized enzymes. This research provides an explanation for how different chemical modifications in an enzyme affect its catalytic activity in ways that are not predictable by static design algorithms.