Towards a Quantum-Mechanical Understanding of Redox Chemistry in Proteins

项目总结/摘要 金属几乎存在于每一种具有生物功能的蛋白质中， 引导新陈代谢和呼吸的化学反应对于改善许多人的结果至关重要。 遗传疾病和用于鉴定新的治疗药物靶点。这些含金属的蛋白质（金属- 酶）适合于通过X射线光谱学来研究，其可以阐明电子在酶作用期间的行为。 金属催化的化学反应，当与量子化学计算配对时， 反应路径的位置。量子化学提供了最微妙和详细的图片， 在所有科学中，电子化学，允许构建无与伦比的洞察力模型。当AD- 同步加速器光源的进步已经将实验X射线光谱学推向了未来， 计算X射线光谱学尚未实现有效性和准确性的充分平衡， 金属酶的研究本文提出的工作将追求一套准确和有效的计算 基于量子化学的X射线光谱学方法。含时密度的最新发展 泛函理论将被扩展到适当地处理代表金属中心的未成对电子 在金属酶中。这种方法将与尖端的波函数分析方法一起使用， 量子化学中的ODS来确定铜原子是否在反应中采用3+氧化态 酪氨酸酶的作用机制体内Cu（III）的存在或缺乏对于指导我们的化学释放至关重要。 金属酶的反应性，但它的存在还没有被直接鉴定艾德在生物系统中。 为了仔细地解决这个问题，将使用理论上更严格的波来设计其他方法。 函数理论（WFT），从而避免了密度泛函固有的近似所带来的潜在误差 理论，并给出了X射线光谱的L边缘部分的访问。结合起来，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 迄今为止报道的路径。这种计算分析将模拟X射线，共振拉曼，和光学。 校准吸收光谱将由实验合作者艾德·所罗门（ES）收集。在寻址之后 铜（III）的问题，铁（IV）-氧代中间体的其他研究将进行类似的 议定书结合量子化学和经验数据的见解， 金属酶催化的中间体将最终被揭示出来。一个高度合作的环境在大学- 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。的 拟议的研究将在马丁·海德-戈登的指导下进行，并得到 斯坦福大学的ES。职业培训计划包括指导研究生，教授课程， 参加关于研究环境中的无障碍环境和赠款写作，网络和表演的研讨会 社区外展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。

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.