Towards a Quantum-Mechanical Understanding of Redox Chemistry in Proteins

对蛋白质氧化还原化学的量子力学理解

• 批准号: 10606459
• 负责人: Kevin Carter-Fenk
• 金额: $ 6.95万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10606459
• 关键词: ATP Synthesis Pathway; Active Sites; Address; Adopted; Affinity; Alzheimer' s Disease; Behavior; Benchmarking; Biochemical; Biochemistry; Biological Process; Biology; Brain; California; Catalysis; Chemicals; Chemistry; Community Outreach; Computer Analysis; Computing Methodologies; Copper; Coupled; Data; Development; Drug Targeting; Educational process of instructing; Educational workshop; Electrons; Encephalopathies; Environment; Enzymes; Equation; Equilibrium; Foundations; Future; Genetic Diseases; Geometry; Grant; Head; Health; Human; Investigation; Iron; Ligands; Light; Linear Accelerator Radiotherapy Systems; Link; Measurement; Melanins; Mentors; Metabolism; Metals; Methods; Modeling; Modernization; Monophenol Monooxygenase; Motion; Optics; Outcome; Oxidases; Oxidation-Reduction; Pathway interactions; Production; Proteins; Protocols documentation; Quantum Mechanics; Reaction; Reporting; Research; Research Personnel; Respiration; Roentgen Rays; Role; Science; Source; Spectrum Analysis; Structure; Synchrotrons; System; Time; Training; United States National Institutes of Health; Universities; Work; Writing; X ray spectroscopy; absorption; biological systems; brain tissue; career; chemical reaction; collaborative environment; computer studies; computing resources; cost; density; design; electron density; electronic structure; graduate student; improved; improved outcome; in vivo; infancy; insight; metabolomics; metalloenzyme; method development; molecular orbital; novel; novel therapeutics; oxidation; quantum chemistry; theories; time use

Project Summary/Abstract Metals are found in almost every protein that serves a biological function, and understanding their role in the chemical reactions that guide metabolism and respiration is critical to improving outcomes for a number of genetic diseases and for identifying new therapeutic drug targets. These metal-containing proteins (metalloen- zymes) are amenable to study via x-ray spectroscopy, which can elucidate the behavior of electrons during metal-catalyzed chemical reactions and, when paired with quantum chemistry calculations, a deep under- standing of the reaction pathways. Quantum chemistry provides the most nuanced and detailed picture of the chemistry of electrons in all of science, allowing for models of unparalleled insight to be constructed. While ad- vances in synchrotron light sources have pushed experimental x-ray spectroscopy into the future, methods for computational x-ray spectroscopy have not yet achieved a sufficient balance of efficiency and accuracy for the study of metalloenzymes. The work proposed herein will pursue a suite of accurate and efficient computational x-ray spectroscopy methods based on quantum chemistry. Recent developments in time-dependent density functional theory will be extended to properly deal with the unpaired electrons that typify the metal centers within metalloenzymes. This approach will then be used alongside cutting-edge wave function analysis meth- ods in quantum chemistry to determine whether copper atoms ever adopt a 3+ oxidation state in the reaction mechanism of tyrosinase. The existence, or lack thereof, of Cu(III) in vivo is critical to guiding our chemical un- derstanding of metalloenzyme reactivity, but its presence has yet to be directly identified in biological systems. To carefully address this question, additional methods will be designed using more theoretically rigorous wave function theory (WFT), thus avoiding potential errors imposed by approximations inherent to density functional theory and giving access to the L-edge part of the x-ray spectrum. Combined, these methods will achieve the most comprehensive computational characterization of copper intermediates in metalloenzyme reaction pathways reported to date. This computational analysis will simulate the x-ray, resonance Raman, and opti- cal absorption spectra that will be collected by experimental collaborator, Ed Solomon (ES). After addressing the question of Cu(III), additional investigations into iron(IV)-oxo intermediates will be pursued with a similar protocol. With the combined insights of quantum chemistry and empirical data, the identity of the chemical intermediates in metalloenzyme catalysis will finally be revealed. A highly collaborative environment at Uni- versity of California, Berkeley (UCB) will allow for frequent interactions with world-class researchers. The proposed research will be carried out under the guidance of Martin Head-Gordon and with the assistance of ES at Stanford University. The career training plan includes mentoring graduate students, teaching courses, attending workshops on accessibility in research environments and grant-writing, networking, and performing community outreach. This training plan will build a strong foundation for a career in health-related research.

项目概要/摘要 几乎所有具有生物功能的蛋白质中都含有金属，了解它们在生物功能中的作用 代谢引导和呼吸的化学反应对于改善许多疾病的结果至关重要 遗传疾病和确定新的治疗药物靶点。 酶）可以通过 X 射线光谱进行研究，它可以阐明电子在酶过程中的行为 金属催化的化学反应，当与量子化学计算相结合时，深入了解 量子化学提供了最细致和详细的图景。 所有科学中的电子化学，允许构建无与伦比的洞察力模型。 同步加速器光源的进步将实验 X 射线光谱学推向了未来， 计算 X 射线光谱学尚未实现效率和精度的充分平衡 本文提出的工作将追求一套准确有效的计算方法。 基于量子化学的 X 射线光谱方法。时间相关密度的最新进展。 泛函理论将扩展到正确处理代表金属中心的不成对电子 然后，该方法将与尖端波函数分析方法一起使用。 量子化学中的 ods，用于确定铜原子在反应中是否采用 3+ 氧化态 体内 Cu(III) 的存在或缺乏对于指导我们的化学反应至关重要。 了解金属酶的反应性，但其存在尚未在生物系统中直接识别。 为了仔细解决这个问题，将使用理论上更严格的波来设计其他方法 函数理论（WFT），从而避免密度泛函固有的近似所带来的潜在错误 结合理论和获取 X 射线光谱的 L 边缘部分，这些方法将实现。 金属酶反应中铜中间体最全面的计算表征 该计算分析将模拟 X 射线、共振拉曼和光学。 校准吸收光谱将由实验合作者 Ed Solomon (ES) 收集。 关于 Cu(III) 的问题，将采用类似的方法对铁(IV)-氧代中间体进行额外的研究 结合量子化学和经验数据的见解，确定了化学物质的身份。 金属酶催化中间体将最终在 Uni- 中展现出来。 加州大学伯克利分校 (UCB) 将允许与世界一流的研究人员进行频繁的互动。 拟议的研究将在 Martin Head-Gordon 的指导下并在 斯坦福大学的ES职业培训计划包括指导研究生、教授课程、 参加有关研究环境中的无障碍性以及资助撰写、网络和表演的研讨会 该培训计划将为健康相关研究的职业生涯奠定坚实的基础。