Computer Simulations of Electron Transfer Proteins

描述(由申请人提供)： 关于电子转移蛋白最耐人寻味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。这一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。重点放在铁硫蛋白上，这是一种普遍存在的蛋白质，参与呼吸、光合作用和生物合成等途径。我们研究的关键问题是HIPIPs中的[4Fe-4S]3/2，铁还蛋白中的[4Fe-4S]2/1，Aim 1中固氮酶Fe蛋白中的[4Fe-4S]1/0，Aim 2中呼吸络合物I中的7个[4Fe-4S]簇内的分子内转移，以及Aim 3中的Fe-S簇组装途径。我们的方法使用了连续介质静电计算、分子动力学模拟、电子结构计算以及序列和结构生物信息学。这一时期的首要目标是开发简单的模型，根据我们在这些蛋白质方面积累的经验，用一些基本参数来描述金属蛋白质的结构。这些模型将被用来开发简单、快速的软件工具，用于预测金属蛋白的氧化还原性质和金属结合部位。此外，这些体系结构模型将用于开发蛋白质介导的电子转移过程模型，这对于大型系统的理论研究是必不可少的，例如呼吸复合体I。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.建立金属蛋白还原势能的结构模型；目标2.建立蛋白质介导的电子转移模型；目标3.建立蛋白质中铁-S簇合物的转化模型 与公共健康相关：对电子转移蛋白的计算研究提供了对代谢过程的基本的分子理解，这些代谢过程在活细胞中传递能量，如呼吸作用和光合作用。这一知识对于了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，呼吸复合体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.