THEORETICAL STUDIES OF METALLOPROTEIN CHROMOPHORES

该提案的目标是发展理论 发色团在生物学上的重要作用 金属蛋白 所采用的方法包括分析 各种类型的光学实验（例如，吸收、共振 拉曼、圆二色性和光化学烧孔）和 精确从头算电子学的新方法 大分子生色团的结构计算 参数化的蛋白质环境，预计将是两个 比传统技术快几个数量级。 的 这些方法的组合将允许确定 重要的电子（交换矩阵元素，激发 能量，氧化和自旋状态，氧化还原电位）和核 （基态和激发态平衡几何，振动力 场）的参数，其表征在 比以前的努力高出上级的水平。 导致的关键因素 增强的结果包括显著改善的数值 算法，与实验组的广泛合作，以及 开发高效的自动化计算机代码。 待研究的金属蛋白包括蓝铜 蛋白质，铁硫蛋白，血红素蛋白，以及 光合反应中心 一个特别的重点将是 电子传递过程;光合初级电荷 分离，将开发详细的动力学模型， 与实验结果相比。 对于其余的蛋白质， 对模型化合物和一系列 相关蛋白质将进行，以建立 发色团性质与光谱的相关性 可观察的 金属蛋白在呼吸电子中的重要性 运输链和氧气运输是不言而喻的。 的 能够可靠地解释体内光谱实验， 这些系统，并建立显着改善的理论 发色团及其与蛋白质相互作用的模型是 发展预测能力的目标的基础， 分子水平上的生物系统。 从长远来看，健康 这样一个研究计划的相关好处是应用 改进的靶向药物设计理论模型 朝向，例如，代谢紊乱 因素的确定 其控制电子传递效率和配体结合， 预测化学改性对 这些特性将极大地促进药物设计过程。

The objective for this proposal is the development of theoretical models for chromophores in biologically important metalloproteins. The methods to be employed include analysis of optical experiments of various types (e.g., absorption, resonance Raman, circular dichroism, and photochemical holeburning) and a novel method for carrying out accurate ab initio electronic structure calculations for large chromophores in a realistically parametrized protein environment which is expected to be two orders of magnitude faster than conventional techniques. The combination of these approaches will allow determination of the important electronic (exchange matrix elements, excitation energies, oxidation and spin states, redox potential) and nuclear (ground and excited state equilibrium geometry, vibrational force fields) parameters which characterize the in vivo chromophore at a level superior to previous efforts. The key factors leading to enhanced results include substantially improved numerical algorithms, extensive collaboration with experimental groups, and development of efficient, automated computer codes. The metalloproteins to be studied include the blue copper proteins, iron-sulfur proteins, heme proteins, and the photosynthetic reaction center. A particular focus will be on electron transport processes; for photosynthetic primary charge separation, a detailed dynamical model will be developed and compared with experimental results. For the remaining proteins, systematic studies of both model compounds and a series of related proteins will be carried out in order to establish correlations of chromophore properties with spectroscopic observables. The importance of metalloproteins in the respiratory electron transport chain and in oxygen transport is self-evident. The ability to reliably interpret in vivo spectroscopic experiments on these systems and to construct significantly improved theoretical models of the chromophore and its interaction with the protein is fundamental to the goal of developing predictive capabilities for biological systems at the molecular level. The long term, health- related benefits of such a research program are the application of the improved theoretical models to the design of drugs targeted towards, e.g., metabolic disorders. Determination of the factors which control electron transport efficiency and ligand binding and the capacity to predict the effects of chemical modifications on these properties should greatly facilitate the drug design process.