Structure and Function of Iron-Sulfur Clusters

描述（由申请人提供）：该项目的总体目标是为生物系统中普遍存在的基于铁硫簇的蛋白质类开发分子力学力场。这些蛋白质作为二氧、一氧化碳和一氧化氮传感器，充当电子转移和氧化还原剂，并具有一些质子转移功能。建立了一系列具有良好晶体结构的铁硫簇基蛋白质的力场参数；另外的模型化合物也将被检查，再次与文献结构信息可用。将进行高级计算，以获得与晶体学数据一致的良好理论结构。我们将首先尝试使用密度泛函理论（DFT）方法进行这些计算，因为这些计算提供了复杂性和速度之间的良好平衡（即使对于大分子系统）。x射线结构和计算的数据将为系统的键长、角度和扭转力常数、Lennard-Jones参数和原子间电荷分布的提取提供充足的数据。这些分量构成了AMBER力场中使用的势函数。最初，我们将寻求扩大这个力场，提出一个参数化的集合，适合于在铁硫基蛋白质上进行分子力学计算器。我们将测试这种分子力学力场的有效性，在结构相似和不相似的铁硫簇蛋白中检查内插值和预测值。我们将分子力学计算结果与x射线结构以及文献中的生成热、偶极矩、键解离能和电离势进行比较。最后，随着新的力场能力的掌握，我们将使用长时间尺度的分子动力学模拟来研究关于铁硫蛋白的重要生物结构和功能问题。这是很有吸引力的，因为由于缺乏足够的力场参数，这种方法尚未普遍应用于铁硫系统。发展快速可靠的模拟蛋白质结构和反应性的方法是研究这些生物学上重要分子的关键工具。这项工作将旨在开发一种适合描述铁硫基蛋白质几何形状的计算方法。已知含铁硫簇分子中的缺陷与线粒体疾病有关，更好地模拟这些系统的能力可能会为帕金森病等疾病提供新的见解。

DESCRIPTION (provided by applicant): The overall goals of this project are to develop a molecular mechanics force field for the iron-sulfur cluster based class of proteins that are ubiquitous in biological systems. These proteins serve as dioxygen, carbon monoxide and nitric oxide sensors, act as electron transfer and redox agents and serve some proton transfer functions. The force field parameters will be established for a series of iron-sulfur cluster based proteins with well established crystal structures; additional model compounds will be examined as well, again with literature structural information available. High level calculations will be conducted to gain good theoretical structures that agree with the crystallographic data. We will first attempt to use density functional theory (DFT) methods for these calculations, due to the good balance between sophistication and speed (even for large molecular systems) offered by these calculations. The data from the x-ray structures and the calculations will provide ample data for the extraction of bond length, angle and torsional force constants, the Lennard-Jones parameters, and the charge distribution among the atoms of the system. These components make up the potential function used in the AMBER force field. Initially, we will seek to augment this force field in coming up with a parameterized set suitable for conducting molecular mechanics calculators on iron-sulfur based proteins. We will test the efficacy of this molecular mechanics force field, checking for both interpolative and predictive value in structurally similar and dissimilar iron-sulfur cluster proteins. We will compare the results of the molecular mechanics calculations with x-ray structures as well as literature heats of formation, dipole moments, bond dissociation energies and ionization potentials. Finally, with the new force field capabilities in hand we will study important biological structure and function questions regarding iron-sulfur proteins using long timescale molecular dynamics simulations in explicit water. This is appealing as this approach has not been generally applied to iron-sulfur systems to due lack of adequate force field parameters. PUBLIC HEALTH RELEVANCE The development of fast and reliable methods for simulating protein structure and reactivity is a crucial tool for studying these biologically important molecules. This work will aim to develop a computational approach suitable for describing the geometry of iron-sulfur based proteins. Defects in iron-sulfur cluster containing molecules are known to be associated with mitochondrial diseases, and the ability to better model these systems may lend new insight into diseases such as Parkinson's.