Computer Simulations of Electron Transfer Proteins

关于电子转移蛋白最有趣的问题之一是蛋白质如何改变给定类型的氧化还原位点的电子转移特性。了解其电子转移特性的结构起源对于理解各种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。本研究的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，这是一种普遍存在的蛋白质，参与各种基本过程，如呼吸，光合作用，生物合成和生物降解。我们的前提是这些蛋白质的还原电位的结构来源主要是主链、极性侧链和溶剂的静电效应。由于极性贡献取决于方向和距离，而且有许多这样的小贡献，它们几乎不可能单独通过结构或突变数据进行分类。我们的研究导致了一种确定这些贡献的策略的发展。这一策略现在将应用于其他蛋白质，这些贡献对活化能的影响将被检查。我们进一步的前提是氧化还原位点的电子结构与环境无关。这将用于确定金属和配体取代和簇转化的影响。然后，所有这些结果将用于定义结构/功能关系。我们的方法使用静电势计算实验结构、分子动力学模拟方法、电子结构方法和序列分析。研究将包括[1Fe]铁氧化还原蛋白、[2Fe-2S] Rieske蛋白和2[4Fe-4S]铁氧化还原蛋白。具体目的如下。目的1。由外球变化引起的E差异的来源将被确定。我们的假设是，序列差异可以通过改变蛋白质极性基团和溶剂的静电贡献来影响E。目标2。由内球变化引起的E差异的来源将被确定。我们的假设是，电子的贡献大约与蛋白质环境无关。目标3。将确定序列对位点间电子转移的影响。我们的假设是序列差异会影响电子转移的重组能。目标4。E序列决定因子、折叠和功能的共同进化将被确定。我们的假设是E的序列决定因子应该在功能相关的蛋白质中保守。

One of the most intriguing questions about electron transfer proteins is how the protein modifies the electron transfer properties of a given type of redox site. Knowledge of the structural origins of their electron transfer properties is crucial in understanding the molecular basis of a variety of metabolic processes, diseases involving these processes, and drug design targeting these processes. The overall goal of this research 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 a variety of fundamental processes such as respiration, photosynthesis, biosynthesis, and biodegradation. Our premise is that the structural origins of the reduction potentials for these proteins are mainly the electrostatic effects of the backbone, polar side chains, and solvent. Since polar contributions depend on both orientation and distance and there are many such small contributions, they are almost impossible sort out by structural or mutational data alone. Our research has led to the development of a strategy for identifying these contributions. This strategy will now be applied to other proteins and the influence of these contributions on activation energies will be examined. Our premise further is that the electronic structure of the redox site is environment independent. This will be used to determine the effects of metal and ligand substitution and cluster conversion. All of these results will then be used to define structure/function relationships. Our approach uses electrostatic potential calculations of experimental structures, molecular dynamics simulation methods, electronic structure methods, and sequence analysis. Studies will be of the [1Fe] rubredoxins, the [2Fe-2S] Rieske proteins, and the 2[4Fe-4S] ferredoxins. The specific aims are as follows. Aim 1. Origins of differences in E due to changes in the outer sphere will be determined. Our hypothesis is that sequence differences can affect E by altering the electrostatic contributions of protein polar groups and solvent. Aim 2. Origins of differences in E due to changes in the inner sphere will be determined. Our hypothesis is that the electronic contribution is approximately independent of the protein environment. Aim 3. Effects of sequence on electron transfer between sites will be determined. Our hypothesis is that sequence differences can affect the reorganization energy for electron transfer. Aim 4. Co evolution of E sequence determinants, fold, and function will be determined. Our hypothesis is that sequence determinants of E should be conserved within functionally related proteins.