FACTOR ANALYTICAL DECONVOLUTION OF MULTICOMPONENT HEME/LIGAND UV/VIS SPECTRA

多组分血红素/配体紫外/可见光谱的因子分析解卷积

• 批准号: 6107375
• 负责人: MARCO Antonio LOPEZ
• 金额: --
• 依托单位: CALIFORNIA STATE UNIVERSITY LONG BEACH
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-08-01 至 1999-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6107375
• 关键词: chemical binding; chemical kinetics; chemical models; chemical structure function; computer program /software; computer simulation; electronic spectra; heme; ligands; mathematical model; myoglobin; statistics /biometry; ultraviolet radiation; visible light

Recent picosecond and nanosecond kinetic studies on the geminate recombination of photodissociated CO to Myoglobin, and Myoglobin mutants, has raised fundamental questions concerning the influence of different factors on the ligand binding processes to hemoproteins specifically, and to metalloproteins in general. We propose to use computational methods such as Density Functional theory, Molecular Mechanics, Molecular Dynamics, and Free Energy Perturbation calculations to study, and characterize, the factors which control ligand binding processes to Myoglobin (Mb) and the simple models thereof. We choose this group of systems because there exist a great deal of structural information on them; a requisite for using the proposed computational techniques. Specifically, we shall focus on the simulation of three factors as they affect the processes described above: 1) The Distal Steric effect, 2) The effect of local polarity, and 3) the effect of solvent. We will characterize these factors by using the AMBER software package to simulate both the equilibrium and kinetic properties of hemes, and Myoglobin. Briefly, the proposed methodology is summarized in the following steps: 1) Extend the current heme force field to the simulation of NO-heme and isocyanide-heme systems. 2) Reproduce trends in the binding affinities of ligands to hemes, Mb and Mb mutants via free-energy perturbation, and decompose these down into steric and electrostatic components. 3) Characterize the motion of the pertinent amino acids near the binding site via molecular dynamics. Initially these calculations will be run in vacuo, then the hemes in solvent, and finally the Myoglobin in solvent, which because of their size, will be done in a limited way. Based on preliminary work with simple heme-ligand systems, we anticipate that the major factors by which hemoproteins control the process of ligand binding are electrostatic, with Van der Waals interactions making a smaller contribution. How the relative importance of these two factors, and perhaps others, vary with binding- site structure, is an important question that needs to be addressed. Our studies will go a long way toward quantifying this structure-function relationship. Major applications of the answers to the questions we pose are in the fields of synthetic blood, activation of hemeproteins by NO, and sickle cell anemia. Training in the use of state-of-the-art molecular modeling software and graphics workstations is becoming essential for scientists today and certainly will be necessary for the next generation of scientists. Students will be trained in the planning, use, and interpretation of the calculations described herein and so will better prepare them for using these tools in the future.

孪晶的皮秒和纳秒动力学研究进展 光解离的CO与肌红蛋白的重组，以及肌红蛋白突变体， 提出了关于不同的影响力的基本问题， 特异性地影响血红素蛋白的配体结合过程的因素，以及 金属蛋白质。 我们建议使用计算方法 如密度泛函理论，分子力学，分子力学， 动力学和自由能微扰计算研究， 表征，控制配体结合过程的因素， 肌红蛋白（Mb）及其简单模型。 我们选择这一组 系统，因为存在大量的结构信息 它们;使用所提出的计算技术的必要条件。 具体来说，我们将重点放在三个因素的模拟，因为它们 影响上述过程：1）远端空间效应，2） 局部极性的影响; 3）溶剂的影响。 我们将 通过使用AMBER软件包来表征这些因素， 模拟血红素的平衡和动力学性质， 肌红蛋白。 简而言之，建议的方法概述于 以下步骤：1）将当前血红素力场扩展到 NO-血红素和异腈-血红素体系模拟。 2)再现趋势 在配体与血红素、Mb和Mb突变体的结合亲和力中， 自由能微扰，并将其分解为空间位阻和 静电组件 3)描述相关运动的特征 通过分子动力学分析结合位点附近的氨基酸。 最初 这些计算将在真空中进行，然后在溶剂中进行血红素， 最后是肌红蛋白在溶剂中，由于它们的大小， 以有限的方式进行。 基于简单血红素配体的初步工作 系统，我们预计，主要因素，血红素蛋白 控制配体结合的过程都是静电作用，用货车 华尔斯相互作用的贡献较小。 如何相对 这两个因素的重要性，也许还有其他因素，随着约束力的不同而不同- 网站结构是一个需要解决的重要问题。 我们 研究将大大有助于量化这种结构-功能 关系 对我们提出的问题的答案的主要应用 属于合成血液、通过NO活化血红素蛋白、 和镰状细胞性贫血 培训使用最先进的分子建模软件， 图形工作站对今天的科学家来说越来越重要， 对下一代的科学家来说肯定是必要的。 学生将接受培训的规划，使用和解释的 这里描述的计算，因此将更好地为使用它们做准备 这些工具在未来。