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.

项目摘要/摘要 金属几乎在具有生物学功能的每种蛋白质中都发现，并了解其在 指导代谢和呼吸的化学反应对于改善许多结果至关重要 遗传疾病和鉴定新的治疗药物靶标。这些含金属的蛋白（金属蛋白 zymes）可以通过X射线光谱法进行研究，该光谱可以阐明电子的行为 金属催化的化学反应，并与量子化学计算配对 反应途径的站立。量子化学提供了最细微和详细的图片 所有科学中电子的化学，允许构建无与伦比的见解模型。而广告 同步子源中的Vances已将实验性X射线光谱推向了未来， 计算X射线光谱尚未实现效率和准确性的舒适平衡 金属酶的研究。本文提出的工作将追求一套准确而有效的计算 X射线光谱法基于量子化学。时间相关密度的最新发展 功能理论将扩展到适当处理代表金属中心的未配对电子设备 在金属酶内。然后将使用此方法与尖端波函数分析Metham一起使用 量子化学中的ODs确定铜原子是否在反应中采用3+氧化态 酪氨酸酶的机理。 cu（iii）在体内的存在或缺乏，对于指导我们的化学物质至关重要 概述了金属酶反应性，但其存在尚未在生物系统中直接鉴定。 为了仔细解决这个问题，将使用更多理论上的波浪设计其他方法 功能理论（WFT），因此避免了通过继承密度功能的近似施加的潜在误差 理论并访问X射线频谱的L边缘部分。结合在一起，这些方法将实现 金属酶反应中铜中间体的最全面的计算表征 迄今为止报告的途径。该计算分析将模拟X射线，共振拉曼和Opti- 实验合作者Ed Solomon（ES）将收集的CAL抽象光谱。解决后 CU（III）的问题，将与类似 协议。通过量子化学和经验数据的综合见解，化学的身份 将在最终揭示金属酶催化中的中间体。 Uni-的高度协作环境 加利福尼亚州伯克利（UCB）的版本将允许与世界一流的研究人员进行经常互动。 拟议的研究将在马丁·盖登（Martin Head-Gordon）的指导下进行，并在 ES在斯坦福大学。职业培训计划包括心理研究生，教学课程， 参加研究环境中的可访问性和赠款，网络和执行的讲习班 社区宣传。该培训计划将为与健康相关的研究职业奠定坚实的基础。