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.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 cAMP和CGMP是两个重要的细胞内第二使者，介导了广泛的细胞过程。除直接激活蛋白激酶外，CAMP和CGMP还通过直接结合与细胞内环核苷酸结合结构域（CNBD）调节几种类型的离子通道的功能（CNBD），该核苷酸门（CNBD）和超极化激活阳离子（HCN）通道的循环核苷酸门（CNBD）的功能。这些离子通道在人类感觉，心血管和中枢神经系统中起着重要作用。每个通道亚基都包含一个六跨膜结构域，C-terminus中的CNBD和两者之间的接头区域。正如每个人都注意到的那样，最近发布的ION通道相关结构已经揭示了对通道功能的大量机械见解。但是，静态图片中的信息始终受到限制。通道相关结构的可用性以及计算方法的最新改进创造了一个秘密机会，以结合研究通道蛋白功能性质的实验和理论技术。当前，我们一直在应用分子动力学模拟和自由能计算来解释生理数据，并就环核苷酸与HCN通道的结合结构域的结合获得了一些有趣的结果。该研究参与了一些用于MD模拟和能量计算的模拟包，例如Gromacs，VMD，APB，Molaris等。 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.我们认为，适当量的计算时间分配将有助于CNG和HCN通道蛋白的生物物理特性的当前研究。