Integrated Computational and Mechanistic Investigation on New Reactivity and Selectivity in Emerging Enzymatic Reactions

在化学结构、动力学和机理B(CSDM-B)计划的支持下，加州大学圣巴巴拉分校的杨阳和匹兹堡大学的刘鹏正在努力整合最先进的计算和实验工具，以研究最近发展的新的自然酶反应中化学、区域和立体选择性的机制和来源。作为数百万年自然进化的产物，酶能够促进其他具有挑战性的反应，并在可持续和环境友好的条件下对这些过程进行精细控制。在过去的几年里，生物催化研究人员利用非自然的电子转移机制，开发了一系列在自然酶学中未知的生物催化反应。尽管最近取得了这些进展，但这些最近发展起来的酶反应的详细机制和选择性的来源仍有待阐明。结合物理有机化学和最先进的计算化学工具，这项研究有望揭示这些新的酶反应产生的机理、反应性和选择性模式。从这些研究中吸取的经验教训可能会为重新装备的生物催化剂开发带来新的设计原则。通过促进以生物技术为重点的实验和计算化学家之间的思想交流，并吸引不同的研究团队，PI杨和刘的目标是协同效应。与此同时，他们正在建立一个强大的跨学科研究环境，以培训未来劳动力中具有重要意义的机械、分子生物催化方面的熟练成员。该奖项支持加州大学圣巴巴拉分校的杨小组和匹兹堡大学的刘小组之间的合作努力。该团队旨在加深对最近开发的立体选择性生物催化自由基反应的基本理解。本研究将结合密度泛函理论(DFT)、分子动力学模拟(MDS)和混合量子力学/分子力学(QM/MM)方法，研究近年来发展起来的辅酶反应中蛋白质调控的电子和原子转移机制。这个项目将开发计算模型，以使酶控制的化学选择性环化反应与最近进化的生物催化剂合理化。通过将机械酶学和计算相结合，这两个研究小组试图阐明双功能生物催化如何作为促进非自然酶反应的一般手段。如果成功，这项研究将在生物催化研究的前沿提供机械论的见解，该研究针对合成应用的从新到自然的转变。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

With support from the Chemical Structure, Dynamics and Mechanisms-B (CSDM-B) Program, Yang Yang at the University of California-Santa Barbara and Peng Liu at the University of Pittsburgh are working to integrate state-of-the-art computational and experimental tools to investigate the mechanisms and origins of chemo-, regio-, and stereoselectivities in recently developed new-to nature enzymatic reactions. As the products of millions of years of natural evolution, enzymes are capable of facilitating otherwise challenging reactions and exerting exquisite control over these processes under sustainable and environmentally friendly conditions. Over the past several years, biocatalysis researchers have capitalized on unnatural electron transfer mechanisms and developed a range of biocatalytic reactions which were not known in natural enzymology. Despite these recent advances, the detailed mechanisms and the origins of selectivity in these recently developed enzymatic reactions remain to be elucidated. Combining physical organic chemistry and the state-of-the-art computational chemistry tools, this research is expected to shed light on the mechanisms, reactivities, and selectivity patterns emerging from these new enzymatic reactions. The lessons learned from these studies will likely lead to new design principles for retooled biocatalyst development. By promoting ideas exchange between experimental and computational chemists with a biotechnology focus and engaging a diverse research team, PIs Yang and Liu are targeting synergy. At the same time, they are building a strong cross-disciplinary research environment to train skilled members of the future workforce in mechanistic, molecular biocatalysis with important implications for biomanufacturing.This award supports a collaborative effort between the Yang group at UC-Santa Barbara and the Liu group at U Pittsburgh. The team aims to further fundamental understanding of recently developed stereoselective biocatalytic radical reactions. Using a combination of density functional theory (DFT), molecular dynamics simulation (MDS), and hybrid quantum mechanics/molecular mechanics (QM/MM) methods, this research will investigate the protein-regulated electron and atom transfer mechanisms in recently developed reactions using cofactor-dependent enzymes. This project will develop computational models to rationalize enzyme-controlled chemoselective cyclizations with recently evolved biocatalysts. By integrating mechanistic enzymology and computation, the two research groups seek to elucidate how bifunctional biocatalysis can serve as a general means to facilitate unnatural enzymatic reactions. If successful, this study will provide mechanistic insight at the forefront of biocatalytic research that is directed at new-to-nature transformations for synthetic application.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.