Computer Simulations of Electron Transfer Proteins

描述（由申请人提供）： 关于电子转移蛋白质最有趣的问题之一是蛋白质如何改变其氧化还原位点的电子转移性质。这些知识对于理解代谢过程的分子基础、涉及这些过程的疾病以及针对这些过程的药物设计至关重要。总体目标是在分子水平上了解电子转移蛋白的性质。重点是铁硫蛋白，它们是参与呼吸、光合作用和生物合成等途径的普遍蛋白质。我们解决的关键问题是在目标1中通过蛋白质稳定HiPPs中的[4Fe-4S]3+/2+、铁氧化还原蛋白中的[4Fe-4S]2+/1+和固氮酶Fe蛋白中的[4Fe-4S]1+/0，在目标2中在呼吸复合物I中发现的7个[4Fe-4S]簇的“线”中的分子内转移，以及在目标3中的Fe-S簇组装途径。我们的方法使用连续静电计算，分子动力学模拟，电子结构计算，序列和结构生物信息学。 在这一时期，最重要的目标是开发简单的模型，描述金属蛋白的结构与一些基本参数的基础上，我们积累的经验与这些蛋白质。该模型将用于开发简单，快速的软件工具，用于预测氧化还原性质和金属蛋白的金属结合位点。此外，这些结构模型将用于开发蛋白质介导的电子转移过程模型，这对于呼吸复合物I等大型系统的理论研究至关重要。这些模型的功能将使用其他计算技术和我们的合作者的实验结果进行测试。此外，这些模型将为设计新的计算和实验提供一个框架。 具体目标是：目标1。建立金属蛋白质还原电位的结构模型.开发蛋白质介导的电子转移模型目标3。开发蛋白质中Fe-S簇转化的模型 公共卫生相关性：电子转移蛋白的计算研究提供了对在活细胞周围移动能量的代谢过程（如呼吸和光合作用）的基本分子理解。这些知识对于理解涉及这些过程的疾病和设计针对这些疾病的药物至关重要。例如，呼吸复合物I的功能障碍与人类神经退行性疾病和衰老有关。

DESCRIPTION (provided by applicant): One of the most intriguing questions about electron transfer proteins is how the protein modifies the electron transfer properties of its redox site. This knowledge is crucial in understanding the molecular basis of metabolic processes, diseases involving these processes, and drug design targeting these processes. The overall goal is to understand the properties of electron transfer proteins at a molecular level. The focus is on the iron-sulfur proteins, which are ubiquitous proteins involved in pathways as respiration, photosynthesis, and biosynthesis. Key issues we address are the stabilization by the protein of [4Fe-4S]3+/2+ in HiPIPs, [4Fe-4S]2+/1+ in ferredoxins, and [4Fe-4S]1+/0 in nitrogenase Fe-protein in aim 1, the intramolecular transfer in the "wire" of seven [4Fe-4S] clusters found in respiratory complex I in aim 2, and the Fe-S cluster assembly pathway in aim 3. Our approach uses continuum electrostatic calculations, molecular dynamics simulations, electronic structure calculations, and sequence and structural bioinformatics. An overriding aim in this period is to develop simple models that describe the architecture of metalloproteins with a few essential parameters based on our accumulated experience with these proteins. The models will be used to develop simple, fast software tools for predicting redox properties and metal binding sites of metalloproteins. In addition, these architectural models will be used in developing process models for protein-mediated electron transfer, which are essential for theoretical studies of large systems such as the respiratory complex I. Features of these models will be tested using other calculation techniques and experimental results from our collaborators. Moreover, these models will provide a framework for designing new calculations and experiments. The specific aims are: Aim 1. Develop an architectural model for reduction potentials of metalloproteins Aim 2. Develop models for protein-mediated electron transfer Aim 3. Develop models for conversion of Fe-S clusters in proteins PUBLIC HEALTH RELEVANCE: Computational studies of electron transfer proteins provide a fundamental, molecular understanding of the metabolic processes that move energy around living cells such as respiration and photosynthesis. This knowledge is crucial in understanding diseases that involve these processes and designing drugs to target these diseases. For instance, dysfunction in respiratory complex I has been associated with human neurodegenerative diseases and aging.