Heme Protein Structure and Dynamics

描述(申请人提供)：将进行结构和功能研究，以便从分子水平了解血红素蛋白在基本生理过程中的作用，包括呼吸、新陈代谢和细胞反应的调节。将特别强调新类别的血红素感受器蛋白。信号转导蛋白CooA和H-NOX家族，以及血红素调节酶胱硫醚β合成酶，已被选作详细的蛋白质构象变化的表征和动态研究。此外，还将研究血红素传感器识别配基的决定因素，特别强调NO的选择性。共振拉曼光谱将被用来作为对血红素基团及其与周围蛋白质和外源配体相互作用的结构监测。动力学研究将利用脉冲探测时间分辨共振拉曼光谱在纳秒和更长的时间尺度上。目前的DFT和QM/MM技术的计算将被用来从光谱中提取最大的信息，并提供对血红素-蛋白质相互作用的分子机制的洞察。血红素蛋白对人类健康至关重要，它们的故障与许多疾病状态有关。血红素蛋白将氧气从肺部输送到组织中，然后将氧气的能量转化为生理上有用的形式。其他血红素蛋白是关键生物过程的调节器。了解血红素蛋白在分子水平上是如何工作的是一个重要的目标，并可能导致新的治疗方法。

DESCRIPTION (provided by applicant): Structural and functional studies will be carried out in order to provide a molecular level of understanding of the role of heme proteins in fundamental physiological processes, including respiration, metabolism, and the regulation of cellular responses. Special emphasis will be placed on the new class of heme sensor proteins. The signal transducers CooA and the H-NOX family of proteins, as well as the heme-regulated enzyme cystathionine beta synthase, have been selected for detailed characterization and dynamical studies of protein conformational change. In addition, the determinants of ligand discrimination by the heme sensors will be studied, with special emphasis on NO selectivity. Resonance Raman spectroscopy will be applied as a structural monitor of the heme group, and of its interaction with the surrounding protein and with exogenous ligands. Dynamical studies will utilize pulse-probe time-resolved resonance Raman spectroscopy on nanosecond and longer time scales. Computation with current DFT and QM/MM techniques will be employed to extract maximum information from the spectra, and to provide insight into the molecular mechanisms of the heme-protein interactions. Heme proteins are critical to human health, and their malfunction is associated with many disease states. Heme proteins ferry oxygen from the lungs to the tissues and then convert oxygen's energy to physiologically useful forms. Other heme proteins are regulators of critical biological processes. Understanding how heme proteins work at the molecular level is an important goal and may lead to new therapies.