Computer Simulations of Electron Transfer Proteins

描述(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部位的电子转移性质。这一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是至关重要的。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，参与了呼吸作用、光合作用、生物合成和生物降解等基本过程。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。我们的研究包括三个基本方面：(1)决定电子转移驱动力的还原电位(E)，(2)蛋白质重组能，它在蛋白质如何如此有效和快速地移动电子方面发挥作用，以及(3)簇转换，它在许多Fe-S蛋白质的功能和形成中起重要作用。研究将主要集中在2[4Fe-4S]铁氧还蛋白和生物素合成酶。具体目标是： 目的1.确定Fe-S蛋白中极性基团导致E差异的来源。我们的工作模型是，氧化还原位上的氢键主要通过氢键施主偶极的静电作用而不是电子微扰来影响E。 目的2.确定铁-S蛋白重组能的性质。我们的工作模型是，序列差异可以通过氢键影响重组能。 目的3.确定铁-S类似物和蛋白质中的簇状转化机制。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.