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

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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 the 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. 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. Recent advances in computational methodologies and the crystal structure of the CNBD of HCN2 channel make a prefect opportunity to combine the experimental and theoretical approaches to tackle the nature of the ligand-gating in HCN/CNG channels. We are using molecular dynamics and other computational techniques to gain more insights into the ligand binding and the conformational coupling to the channel opening. Preliminary data from molecular dynamics simulation of the CNBD and the electrophysiological characterization of mutant HCN2 channels provided many insights and helped to clarify several important issues. We believe that the allocation of appropriate amount of computational time would facilitate the current simulation projects dramatically and help to obtain a deeper understanding of the ligand-gating in CNG and HCN channels.