Structure, Spectra, and Roles of Metal and Active Site in HNO Heme Protein Comple

HNO 血红素蛋白复合物中金属和活性位点的结构、光谱和作用

• 批准号: 7516079
• 负责人: Yong Zhang
• 金额: $ 7.08万
• 依托单位: UNIVERSITY OF SOUTHERN MISSISSIPPI
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-18 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7516079
• 关键词: Active Sites; Alkanes; Appendix; Biological; Biological Models; Biological Process; Blood - brain barrier anatomy; Blood Vessels; Cells; Characteristics; Chemicals; Class; Complex; Data; Disease; Disruption; Exhibits; Frequencies; Future; Health; Heart failure; Hemeproteins; Hydrogen Bonding; Investigation; Ligands; Metalloproteins; Metals; Methods; Modeling; Myoglobin; Names; Nervous System Physiology; Neutrophil Infiltration; Numbers; Oxidative Stress; Physiological; Physiological Processes; Physiological reperfusion; Principal Investigator; Property; Proteins; Public Health; Quantum Mechanics; Range; Regulation; Relaxation; Reperfusion Therapy; Research; Roentgen Rays; Role; Siblings; Signaling Molecule; Stroke; Structure; Therapeutic; Vasodilator Agents; Work; absorption; enzyme activity; improved; metal complex; programs; quantum; renal ischemia

DESCRIPTION (provided by applicant): HNO has distinctive roles in many biological processes, such as vascular relaxation, enzyme activity regulation, and neurological function regulation. Its pharmacological effects include enhanced cell oxidative stress, blood-brain barrier disruption and neutrophil infiltration during renal ischemia/reperfusion. The preferential vasodilative effect exhibited by HNO compared to its sibling signaling molecule NO makes HNO donors a potential new class of vasodilators and heart failure treatments. Many of the biological effects of HNO are involved with heme proteins and other metalloproteins. Structural information of the HNO protein complexes is necessary for understanding the physiological and pharmacological functions of HNO. However, there are currently no crystal structures of HNO protein complexes. The overall objective of this work is to investigate the structure, characteristic spectroscopic data, and the roles of metal and active site in the only isolated HNO protein complex, MbHNO (Mb = myoglobin), and related heme protein complexes and HNO metal complexes using high accuracy quantum mechanics methods. The first specific aim is to establish quantum chemical methods that can accurately reproduce the broad range of experimental NMR shifts and vibrational frequencies seen in HNO metal complexes, including heme protein model systems, and determine the effects of metal and ligand set on the HNO stability and spectra. The second specific aim is to conduct a comprehensive investigation of possible active site models of MbHNO, with different hydrogen bonding modes for the HNO moiety, different scales of nearby residues, and different ligand orientations. A geometric structure that quantitatively agrees with experimental NMR, vibrational, and X-ray absorption spectroscopic data will be determined for MbHNO. Effects of HNO interactions with nearby residues in the active site on the MbHNO geometry, HNO stabilization energy, and spectroscopic properties, as well as comparisons with MbNO, MbO2, and RNO (R = alkane and arene) heme protein complexes will be examined to improve our understanding of the functional role of the active site. Results will provide useful details of the structural, spectral and functional aspects of HNO interactions with metal centers in proteins and models, which will assist in future studies of health, diseases, and therapeutic treatments involving HNO. PUBLIC HEALTH RELEVANCE: This project will provide useful details of structural, spectral and functional aspects of HNO interactions with metal centers in proteins. Since HNO participates in a broad range of physiological processes related to health, has extensive pharmacological effects, and offers a promising new treatment for diseases such as heart failure and stroke, results from this project will assist future studies of health, diseases, and therapeutic treatments involving HNO.

描述（由申请人提供）：HNO在许多生物学过程中具有独特的作用，例如血管松弛，酶活性调节和神经功能调节。它的药理作用包括增强的细胞氧化应激，肾脏缺血/再灌注期间的血脑屏障破坏和中性粒细胞浸润。与其兄弟姐妹信号分子没有相比，HNO表现出的优先血管扩张效应使HNO供体成为潜在的新型血管扩张剂和心力衰竭处理。 HNO的许多生物学作用都与血红素蛋白和其他金属蛋白有关。 HNO蛋白复合物的结构信息对于理解HNO的生理和药理功能是必要的。但是，目前尚无HNO蛋白复合物的晶体结构。这项工作的总体目的是研究唯一孤立的HNO蛋白质复合物，MBHNO（MB =肌球蛋白）以及使用高的血红素蛋白复合物和HNO金属配合物在唯一孤立的HNO蛋白质复合物中金属和活性位点的作用的结构，特征性光谱数据以及金属和活性位点的作用精度量子力学方法。第一个具体目的是建立可以准确地重现HNO金属复合物（包括血红素蛋白模型系统）的广泛实验NMR偏移和振动频率的量子化学方法，并确定了金属和配体对HNO稳定性和HNO稳定性的影响光谱。第二个具体目的是对MBHNO的可能活动现场模型进行全面研究，其氢键模式不同，用于HNO部分，附近残基的不同尺度和不同的配体方向。对于MBHNO，将确定与实验性NMR，振动和X射线吸收光谱数据的几何结构。 HNO与附近残基在活性位点上的相互作用在MBHNO几何形状，HNO稳定能和光谱特性以及与MBNO，MBO2和RNO（R = Alkane和Arene）的比较中的影响我们对活动部位的功能作用的理解。结果将为蛋白质和模型中金属中心的HNO相互作用的结构，光谱和功能方面提供有用的细节，这将有助于对涉及HNO的健康，疾病和治疗治疗的未来研究。公共卫生相关性：该项目将提供与蛋白质金属中心相互作用的结构，光谱和功能方面的有用细节。由于HNO参与了与健康相关的广泛生理过程，具有广泛的药理作用，并为诸如心力衰竭和中风等疾病提供了有希望的新治疗方法，因此该项目的结果将有助于对未来的健康，疾病和治疗治疗的研究涉及HNO。