A COMBINED COMPUTATIONAL AND PHYSIOLOGICAL STUDY ON THE LIGAND-GATING IN CNG AN

CNG AN 配体门控的计算和生理学联合研究

• 批准号: 7601416
• 负责人: Lei Zhou
• 金额: $ 0.03万
• 依托单位: CARNEGIE-MELLON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7601416
• 关键词: Binding; Cardiovascular system; Cell physiology; Computer Retrieval of Information on Scientific Projects Database; Computing Methodologies; Coupling; Cyclic AMP; Cyclic GMP; Cyclic Nucleotides; Data; Free Energy; Funding; Grant; Homologous Protein; Human; Institution; Intracellular Second Messenger; Ion Channel; Ligand Binding; Ligands; Mediating; Molecular Conformation; Nature; Neuraxis; Pathway interactions; Physiological; Play; Property; Protein Kinase; Proteins; Psychological Techniques; Publishing; Range; Research; Research Personnel; Resources; Role; Second Messenger Systems; Sensory; Source; Structure; Time; Transmembrane Domain; United States National Institutes of Health; base; hyperpolarization-activated cation channel; insight; interest; molecular dynamics; protein function; protein structure; simulation; voltage

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. cAMP and cGMP are two important intracellular second messengers mediating a wide range of cellular processes. Other than direct activating protein kinases, cAMP and cGMP also modulate the function of several types of ion channels through the direct binding to the intracellular cyclic-nucleotide binding domain (CNBD) of cyclic-nucleotide gated (CNG) and hyperpolarization-activated cation (HCN) channels. These ion channels play important roles in the human sensory, cardiovascular and central nervous systems. Each channel subunit contains a six-transmembrane domain, a CNBD in the C-terminus and a linker region in between. As everyone noticed, recently published ion channel related structures have revealed so much mechanistic insights into the channel function. However, the information from a static picture is always limited. The availability of channel-related structures and the recent improvement in computational methodologies create a prefect opportunity to combine the experimental and theoretical techniques to study the nature of channel protein function. Currently, we have been applying molecular dynamics simulation and free energy calculations to interpret the physiological data and got some interesting results about the binding of cyclic-nucleotides to the binding domain of HCN channel. Several simulation packages for MD simulation and energetic calculations, such as GROMACS, VMD, APBS, MOLARIS etc., are involved in the research. Furthermore, it is also interesting to build the whole channel structures for CNG and HCN channels, based on the homologous protein structures, including the transmembrane domain of Kv1.2 and the CNBD of HCN2, to gain more insights into the gating mechanisms, especially the conformation changes related to ligand binding and the coupling of ligand-gating to voltage-gating pathways. We believe that the allocation of appropriate amount of computational time would facilitate the current research of the biophysical properties of the CNG and HCN channel proteins dramatically.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 环磷酸腺苷和环磷酸鸟苷是两种重要的细胞内第二信使，介导多种细胞过程。除了直接激活蛋白激酶，cAMP和cGMP还通过直接结合到环核苷酸门控（CNG）和超极化激活阳离子（HCN）通道的细胞内环核苷酸结合结构域（CNBD）来调节几种类型的离子通道的功能。这些离子通道在人体感觉、心血管和中枢神经系统中发挥重要作用。每个通道亚基包含六个跨膜结构域、C末端的CNBD和其间的接头区。正如大家所注意到的，最近发表的离子通道相关结构揭示了如此多的通道功能的机制见解。然而，从静态图像中获得的信息总是有限的。通道相关结构的可用性和最近计算方法的改进为联合收割机结合实验和理论技术研究通道蛋白功能的本质创造了一个完美的机会。目前，我们已经应用分子动力学模拟和自由能计算来解释生理数据，并得到了一些有趣的结果，环核苷酸结合到HCN通道的结合域。多种用于MD模拟和能量计算的模拟软件包，如GROMACS、VMD、APBS、MOLARIS等，参与了这项研究。此外，基于同源蛋白质结构，包括Kv1.2的跨膜结构域和HCN 2的CNBD，构建CNG和HCN通道的整个通道结构也是有趣的，以获得更多的门控机制，特别是与配体结合相关的构象变化以及配体门控与电压门控途径的耦合。我们相信，适当的计算时间的分配将大大促进目前的CNG和HCN通道蛋白的生物物理特性的研究。