Computer Simulations of Electron Transfer Proteins

描述（由申请人提供）：关于电子转移蛋白质的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。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，这是普遍存在的蛋白质参与的基本过程，如呼吸，光合作用，生物合成和生物降解。我们的方法使用静电势计算，分子动力学模拟，电子结构计算和序列分析。我们的研究涵盖了三个基本领域：（1）还原电位（E），它决定了电子转移的驱动力，（2）蛋白质重组能，它必须在蛋白质如何有效和快速地移动电子中发挥作用，以及（3）簇转换，这在许多Fe-S蛋白质的功能和形成中很重要。主要研究2[4Fe-4S]铁氧化还原酶和生物素合成酶。具体目标是： 目标1。将确定由于Fe-S蛋白中的极性基团而导致的E差异的起源。我们的工作模型是，氢键的氧化还原位点影响E主要是由静电的氢键供体偶极子，而不是由电子扰动。 目标二。铁硫蛋白的重组能的性质将被确定。我们的工作模型是序列差异可以通过氢键影响重组能。 目标3。将确定Fe-S类似物和蛋白质中簇转换的机制。我们的工作模型是自旋离域和氧化还原态是重要的。

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 a variety 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 fundamental processes such as respiration, photosynthesis, biosynthesis, and biodegradation. Our approach uses electrostatic potential calculations, molecular dynamics simulations, electronic structure calculations, and sequence analysis. Our studies cover three essential areas: (1) the reduction potentials (E), which determine the driving force for electron transfer, (2) the protein reorganization energy, which must play a role in how proteins can move electrons so efficiently and quickly, and (3) cluster conversion, which is important in the function and formation of many Fe-S proteins. Studies will be mainly on the 2[4Fe-4S] ferredoxins and biotin synthase. The specific aims are: Aim 1. The origins of differences in E due to polar groups in Fe-S proteins will be determined. Our working model is that hydrogen bonds to the redox site affect E mainly by the electrostatics of the hydrogen bond donor dipole rather than by electronic perturbation. Aim 2. The nature of the reorganization energy of Fe-S proteins will be determined. Our working model is that sequence differences can affect the reorganization energy via hydrogen bonds. Aim 3. The mechanisms of cluster conversion in Fe-S analogs and proteins will be determined. Our working model is that spin delocalization and redox state are important.