Theoretical Investigations of Interactions of Ligands with Various Hemoproteins

配体与各种血红素蛋白相互作用的理论研究

• 批准号: 7655509
• 负责人: John D. Watts
• 金额: $ 18.25万
• 依托单位: JACKSON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7655509
• 关键词: Accounting; Address; Adopted; Affinity; Alkanes; Arts; Asphyxia; Attention; Azides; Binding; Biochemical; Biology; Blood Vessels; Characteristics; Chemicals; Chemistry; Code; Complex; Computer Simulation; Computer software; Cytochromes; Discrimination; Electron Transport; Environment; Family; Heavy Metals; Heme; Heme Group; Hemeproteins; Hemoglobin; Human; Hybrids; Hydroxylation; Investigation; Kinetics; Life; Ligand Binding; Ligands; Lung; Metabolism; Metals; Methodology; Methods; Mixed Function Oxygenases; Modeling; Molecular; Mono-S; Muscle; Mutation; Myoglobin; Organism; Oxidases; Oxides; Oxygen; Oxygenases; Peroxidases; Play; Property; Prosthesis; Proteins; Quantum Mechanics; Reaction; Reporting; Research; Role; Soluble Guanylate Cyclase; Structure; System; Theoretical Studies; Work; biological systems; catalase; computerized tools; density; electronic structure; insight; interest; intermolecular interaction; molecular mechanics; oxygen transport; polypeptide; programs; quantum; respiratory; small molecule; theories; tool

DESCRIPTION (provided by applicant): Hemoproteins play essential roles in a wide range of biological systems, including oxygen transport and storage (hemoglobin and myoglobins), oxygen metabolism (oxidases, peroxidases, catalases, and hydroxylases), and electron transfer (cytochromes). This proposal is for a state-of-the-art theoretical study of the interaction of several biologically relevant small-molecule ligands with various hemoproteins. In addition to describing the ligand-heme interaction with advanced density-functional theory (DFT) methodology, the proposed work will model the interaction with the protein environment. The latter is thought to be vital for the various functions of hemoproteins, but its role is not well understood. It has received little attention in theoretical studies, in part because of the large computational demands of doing so. We propose to study the ligand, the heme group, and their interaction with the protein environment using hybrid quantum mechanics/molecular mechanics (QM/MM) methodology. The QM treatment will be performed using DFT, augmented with a recently developed correction for dispersion interactions, with which a reliable description of intermolecular interactions (e.g. between the protein environment and the ligand-heme complex) is possible. The QM treatment will be performed on the ligand, heme, and the closest protein residues. The Amsterdam Density Functional (ADF) and Gaussian03 software will be used. The effect of the protein environment on four properties will be investigated: (1) The structure, interaction energy, and kinetic parameter for the binding of XO molecules (X = O, C, N) to Mb; (2) The ligand selectivity of soluble guanylate cyclase (sGC)-like heme domains; (3) The structure and energetics of the active intermediates in the catalytic cycle of cytochrome P450s; (4) The electronic structure of heme oxygenase complexes with azide, OH, and OOH species. Hemoproteins are critical components of many living systems, including humans. They consist of two parts, the metal-containing heme part and the protein part. The proposed work is a computational modeling study of hemoproteins that will include the protein part in the model. The results will provide information on how their different protein parts enable different hemoproteins to perform their specific functions.

描述（由申请人提供）：血蛋白在广泛的生物系统中起重要作用，包括氧运输和储存（血红蛋白和肌球蛋白），氧代谢（氧化酶，过氧化物酶，催化酶和羟基酶）和电子转移（氧化酶，氧化酶，过氧化物酶，催化酶，催化酶，催化酶，催化酶，催化酶，催化酶）。该建议是针对几个生物学相关的小分子配体与各种血蛋白的相互作用的最新理论研究。除了描述与高级密度功能理论（DFT）方法的配体 - 气味相互作用外，所提出的工作还将对与蛋白质环境的相互作用进行建模。后者被认为对血蛋白的各种功能至关重要，但其作用尚未得到充分理解。它在理论研究中很少关注，部分原因是这样做的计算要求很大。我们建议使用混合量子力学/分子力学（QM/mm）方法研究配体，血红素组及其与蛋白质环境的相互作用。 QM处理将使用DFT进行，并通过最近开发的分散相互作用进行校正，与分子间相互作用（例如蛋白质环境与配体 - 调节复合物之间）的可靠描述是可能的。 QM处理将在配体，血红素和最接近的蛋白质残基上进行。将使用阿姆斯特丹密度功能（ADF）和高斯03软件。将研究蛋白质环境对四个特性的影响：（1）XO分子（X = O，C，N）与MB结合的结构，相互作用能和动力学参数； （2）可溶性鸟苷酸环化酶（SGC）类似血红素域的配体选择性； （3）在细胞色素P450s的催化循环中活性中间体的结构和能量； （4）血红素氧化酶复合物与叠氮化物，OH和OOH物种的电子结构。 血蛋白是包括人类在内的许多生活系统的关键组成部分。它们由两个部分组成，含金属的血红素部分和蛋白质部分。拟议的工作是一项针对蛋白质的计算建模研究，其中将包括模型中的蛋白质部分。结果将提供有关其不同蛋白质零件如何使不同的血蛋白能够执行其特定功能的信息。