Structure and Function of Iron-Sulfur Clusters

铁硫团簇的结构和功能

• 批准号: 7677891
• 负责人: MICHAEL N WEAVER
• 金额: $ 5.17万
• 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/7677891
• 关键词: Amber; Attention; Biological; Biological Models; Biological Process; Carbon; Carbon Dioxide; Carbon Monoxide; Charge; Computing Methodologies; Data; Databases; Defect; Development; Dioxygen; Disease; Dissociation; Electron Transport; Electrostatics; Elements; Equilibrium; Ferredoxin; Goals; Hand; Heating; Iron; Iron-Sulfur Proteins; Length; Literature; Metabolism; Methods; Mitochondrial Diseases; Modeling; Molecular; Nitric Oxide; Organism; Oxidation-Reduction; Oxidoreductase; Oxygen; Parkinson Disease; Pathway interactions; Potential Energy; Predictive Value; Process; Proteins; Protons; Reaction; Series; Simulate; Speed; Structure; Sulfur; Superoxides; System; Theoretical Studies; Thioredoxin; Water; Work; base; biological systems; density; dipole moment; efficacy testing; electronic structure; insight; ionization; molecular dynamics; molecular mechanics; protein structure; public health relevance; 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（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。这些蛋白质作为分子氧，一氧化碳和一氧化氮传感器，作为电子转移和氧化还原剂，并提供一些质子转移功能。力场参数将建立一系列铁硫簇基蛋白质与完善的晶体结构;其他模型化合物也将进行检查，再次与文献结构信息可用。将进行高水平的计算，以获得与晶体学数据一致的良好的理论结构。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（即使对于大分子系统）之间的良好平衡。从X射线结构和计算的数据将提供充足的数据为提取键长，角和扭转力常数，Lennard-Jones参数，和系统的原子之间的电荷分布。这些分量构成了AMBER力场中使用的势函数。最初，我们将寻求增加这个力场，以提出一个适合于对铁硫基蛋白质进行分子力学计算的参数化集合。我们将测试这种分子力学力场的有效性，检查结构相似和不相似的铁硫簇蛋白的插值和预测值。我们将比较的分子力学计算的结果与X-射线结构，以及文献热的形成，偶极矩，键离解能和电离势。最后，随着新的力场能力在手，我们将研究重要的生物结构和功能的问题，铁硫蛋白使用长时间尺度的分子动力学模拟明确的水。这是有吸引力的，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。开发快速可靠的方法来模拟蛋白质结构和反应性是研究这些生物重要分子的重要工具。这项工作的目的是开发一种计算方法，适合于描述铁硫基蛋白质的几何形状。已知含有铁硫簇的分子的缺陷与线粒体疾病有关，并且更好地模拟这些系统的能力可能会对帕金森病等疾病提供新的见解。