Computer Simulations of Electron Transfer Proteins

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给定类型的氧化还原位点的电子转移性质。了解其电子转移性质的结构起源对于了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。这项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。重点放在铁硫蛋白上，这是一种普遍存在的蛋白质，参与各种基本过程，如呼吸作用、光合作用、生物合成和生物降解。我们的前提是，这些蛋白质还原电势的结构来源主要是主链、极性侧链和溶剂的静电效应。由于极地的贡献取决于方位和距离，而且有许多这样的小贡献，仅凭结构或突变数据几乎不可能对它们进行分类。我们的研究导致了确定这些贡献的战略的制定。这一策略现在将应用于其他蛋白质，并将检查这些贡献对激活能的影响。我们的前提是氧化还原位的电子结构与环境无关。这将被用来确定金属和配体取代以及簇合物转化的影响。然后，所有这些结果都将用于定义结构/功能关系。我们的方法使用了实验结构的静电势计算、分子动力学模拟方法、电子结构方法和序列分析。将研究[1Fe]Rubredoxins、[2Fe-2S]Rieske蛋白质和2[4Fe-4S]铁氧还蛋白。具体目标如下。目标1.将确定由于外球变化而导致的E差异的来源。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.将确定由于内部球体变化而导致的E的差异的来源。我们的假设是，电子的贡献大致与蛋白质的环境无关。目的3.确定序列对位置间电子转移的影响。我们的假设是，序列差异会影响电子转移的重组能。目的4.确定E序列决定簇、折叠和功能的共同进化。我们的假设是，E的序列决定因素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.