Development of Bio-inspired Synthetic Metallohydrolases Based on Theoretical Insights

基于理论见解的仿生合成金属水解酶的开发通过与水反应来破坏肽（小蛋白质）和其他生物重要分子中的化学键是很重要的。这种反应被称为水解，在广泛的生物，生物技术和工业应用中起着关键作用。自然界已经设计出高度专业化的酶，称为金属水解酶，以实现这些反应。然而，大多数天然酶仅在特定条件下起作用。开发高效、环境友好和经济的模拟天然酶的分子是非常可取的。它们的设计和合成是一个具有挑战性的研究课题，需要跨学科的合作。在这个项目中，迈阿密大学的Prabhakar教授正在发展对水解的基本理解，并将其应用于合成金属水解酶的设计。这项研究将这些过程中涉及的基本化学反应与潜在的生物，生物技术和工业应用联系起来。Prabhakar博士还为高中和本科阶段的少数群体成员提供教育和研究机会。这些外联活动包括迈阿密戴德县公立学校的荣誉和执行实习计划（HEIP），美国化学学会的项目SEED（经济困难者的夏季经验），夏季研讨会（CATCH：高中计算和理论化学）和高中研究通讯（HRN）。此外，本科生通过两门专业课程和一个夏季研究计划进行研究。在化学系化学催化计划的资助下，迈阿密大学的Rajeev Prabhakar教授正在推导肽（-（O=）C-NH-）和磷酸酯（（O=）（RO）（P-O-R））水解的指导原则，用于开发高效的生物启发合成金属水解酶。与天然酶相比，这些类似物可能具有以下优点：（1）便宜且可回收，（2）尺寸较小，空间限制很少或没有空间限制，以及（3）可针对特定功能进行调节。然而，它们的发展所需的关键结构和机理信息不能通过现有的实验技术容易地获得。在这项研究中，几个国家的最先进的理论和计算化学技术，涉及分子动力学，量子力学（QM）和混合量子力学/分子力学（QM/MM）与实验相结合，首先推导出肽和磷酸酯水解的指导原则，然后将它们应用于设计廉价，环境友好，高效，特异性和催化类似物。这些计算也验证了不同的密度泛函理论（DFT）的泛函，力场参数，和混合QM/MM和QM/QM/MM方法与机械和电子嵌入方案的金属水解酶及其合成类似物的适用性。为了支持该项目的更广泛影响，Prabhakar博士通过迈阿密戴德县公立学校的荣誉和执行实习计划（HEIP）、美国化学学会的SEED项目，（夏季经验的经济障碍），夏季讲习班称为赶上计算和理论化学高中和高中研究通讯（HRN）。本科生参与由NSF和现有的夏季计划和迈阿密大学的专业课程支持的研究。

Development of Bio-inspired Synthetic Metallohydrolases Based on Theoretical Insights The breaking of chemical bonds in peptides (small proteins) and other biologically-important molecules by reaction with water is important. This reaction, known as hydrolysis, plays a critical role in a wide range of biological, biotechnological, and industrial applications. Nature has devised highly specialized enzymes known as metallohydrolases to enable these reactions. However, most of the natural enzymes work only under specific conditions. The development of efficient, environmentally-friendly, and economical molecules that mimic the natural enzymes is highly desirable. Their design and synthesis is challenging topic of research that requires interdisciplinary cooperation. In this project, Professor Prabhakar, University of Miami, is developing a fundamental understanding of hydrolysis and applying it to the design of synthetic metallohydrolases. This research links the basic chemical reactions involved in these processes to potential biological, biotechnological, and industrial applications. Dr. Prabhakar is also providing educational and research opportunities to members of minority groups at the high school and undergraduate levels. These outreach activities include the Honors and Executive Internship Program (HEIP) of the Miami-Dade County Public Schools, the American Chemical Society's Project SEED (Summer Experiences for the Economically Disadvantaged), a summer workshop (CATCH: Computational and Theoretical Chemistry for High School) and a High School Research Newsletter (HRN). Additionally, undergraduate students are conducting research through two specialized courses and a summer research program. With funding from the Chemical Catalysis Program of the Chemistry Division, Professor Rajeev Prabhakar of the University of Miami is deriving guiding principles of peptide (-(O=)C-NH-) and phosphoester ((O=)(RO)(RO)(P-O-R)) hydrolysis for the development of efficient bio-inspired synthetic metallohydrolases. These analogues are likely to offer the following advantages over natural enzymes: (1) inexpensive and recyclable, (2) smaller in size with little or no steric constraints, and (3) tunable for specific functions. However, the critical structural and mechanistic information required for their development cannot be readily obtained through existing experimental techniques. In this research, several state-of-the-art theoretical and computational chemistry techniques involving molecular dynamics, quantum mechanics (QM) and hybrid quantum mechanics/molecular mechanics (QM/MM) are integrated with experiments to first derive the guiding principles of peptide and phosphoester hydrolysis and then apply them to design inexpensive, environment friendly, efficient, specific, and catalytic analogues. These calculations are also validating the applicability of different Density Functional Theory (DFT) functionals, force field parameters, and hybrid QM/MM and QM/QM/MM methods with mechanical and electronic embedding schemes on metallohydrolases and their synthetic analogues. In support of the broader impacts of the project, Dr. Prabhakar is actively training and engaging current and future generations of students at the graduate, undergraduate and high school levels from socio-economically- and educationally-disadvantaged families through the Honors and Executive Internship Program (HEIP) of Miami-Dade County Public Schools, the American Chemical Society's Project SEED (Summer Experiences for the Economically Disadvantaged), a summer workshop called CATCH-Computational and Theoretical Chemistry for High School and a High School Research Newsletter (HRN). The undergraduate students are involved in research supported by the NSF and an existing summer program and specialized courses at the University of Miami.