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

描述（申请人提供）：HNO在许多生物过程中具有独特的作用，如血管舒张、酶活性调节和神经功能调节。其药理作用包括肾缺血/再灌注期间细胞氧化应激增强、血脑屏障破坏和中性粒细胞浸润。与其同胞信号分子NO相比，HNO表现出的优先血管扩张作用使HNO供体成为一类潜在的新的血管扩张剂和心力衰竭治疗药物。HNO的许多生物学效应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。然而，目前还没有HNO蛋白复合物的晶体结构。这项工作的总体目标是调查的结构，特征光谱数据，和金属和活性位点的作用，在唯一的分离HNO蛋白质复合物，MbHNO（Mb =肌红蛋白），相关的血红素蛋白质复合物和HNO金属复合物使用高精度量子力学方法。第一个具体的目标是建立量子化学方法，可以准确地再现广泛的实验NMR位移和振动频率中看到的HNO金属络合物，包括血红素蛋白质模型系统，并确定金属和配体集上的HNO稳定性和光谱的影响。第二个具体的目标是进行全面的调查可能的活性位点模型的MbHNO，不同的氢键模式的HNO部分，不同规模的附近的残基，和不同的配体取向。定量同意实验NMR，振动和X-射线吸收光谱数据的几何结构将被确定为MbHNO。HNO与附近残基的相互作用的影响在活性位点上的MbHNO的几何形状，HNO的稳定能量，和光谱特性，以及比较与MbNO，MbO 2，和RNO（R =烷烃和芳烃）血红素蛋白复合物将检查，以提高我们的理解的活性位点的功能作用。结果将提供有用的细节的HNO与金属中心的蛋白质和模型，这将有助于在未来的研究健康，疾病和治疗性治疗涉及HNO的相互作用的结构，光谱和功能方面。公共卫生相关性：这个项目将提供有用的细节的结构，光谱和功能方面的HNO与金属中心的蛋白质相互作用。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，并为心力衰竭和中风等疾病提供了有前途的新治疗方法，因此该项目的结果将有助于未来对健康，疾病和涉及HNO的治疗方法的研究。

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.