Structure and Function of Iron-Sulfur Clusters

铁硫团簇的结构和功能

• 批准号: 7544638
• 负责人: MICHAEL N WEAVER
• 金额: $ 4.96万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7544638
• 关键词: Amber; Attention; Biological; Biological Models; Biological Process; Carbon; Carbon Dioxide; Carbon Monoxide; Charge; Class; Computing Methodologies; Data; Databases; Defect; Development; Dioxygen; Disease; Dissociation; Electron Transport; Electronics; Electrostatics; Elements; Equilibrium; Ferredoxin; Goals; Hand; Heating; Iron; Iron-Sulfur Proteins; Length; Literature; Metabolism; Methods; Mitochondrial Diseases; Modeling; Molecular; Nitric Oxide; Object Attachment; Organism; Oxidation-Reduction; Oxidoreductase; Oxygen; Parkinson Disease; Pathway interactions; Potential Energy; Predictive Value; Process; Proteins; Protons; Public Health; Reaction; Series; Simulate; Speed; Structure; Sulfur; Superoxides; System; Testing; Theoretical Studies; Thinking; Thioredoxin; Water; Work; base; density; dipole moment; insight; ionization; molecular dynamics; molecular mechanics; protein structure; sensor; simulation; theories; tool

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.

描述(申请人提供)：这个项目的总体目标是为生物系统中普遍存在的基于铁-硫簇的一类蛋白质开发一个分子力学力场。这些蛋白质作为氧气、一氧化碳和一氧化氮的感受器，作为电子传递和氧化还原试剂，并具有一定的质子传递功能。将为一系列具有良好晶体结构的基于铁-硫簇的蛋白质建立力场参数；还将检查其他模型化合物，同样利用现有的文献结构信息。将进行高水平计算，以获得与结晶学数据相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(即使是对于大分子系统)。从X射线结构和计算得到的数据将为提取键长、角度和扭转力常数、Lennard-Jones参数以及体系原子间的电荷分布提供充足的数据。这些分量构成了琥珀力场中使用的势函数。首先，我们将寻求增强这个力场，提出一个适合于进行基于铁-硫基蛋白质的分子力学计算器的参数化集。我们将测试这种分子力力场的有效性，检查在结构相似和不同的铁-硫簇蛋白中的内插和预测价值。我们将把分子力学计算的结果与X射线结构以及文献中的生成热、偶极矩、键离解能和电离势进行比较。最后，有了新的力场能力，我们将在显性水中使用长时间尺度的分子动力学模拟来研究有关铁-硫蛋白质的重要生物结构和功能问题。这是很吸引人的，因为由于缺乏足够的力场参数，这种方法还没有普遍应用于铁硫系统。与公众健康相关发展快速而可靠的模拟蛋白质结构和反应的方法是研究这些具有生物重要性的分子的重要工具。这项工作的目的是开发一种适合描述基于铁-硫基蛋白质的几何结构的计算方法。已知含有铁-硫簇分子的缺陷与线粒体疾病有关，而对这些系统进行更好地建模的能力可能会为帕金森氏症等疾病提供新的见解。