The CB1 Cannabinoid Receptor Activation By Protein Molecular Dynamics Simulations

描述（由申请人提供）：本导师研究科学家发展奖（K01）旨在发展北卡罗莱纳中央大学朱利叶斯L.钱伯斯生物医学/生物技术研究所（jlc - bri）的沈仲渊博士的研究项目。为了实现科学目标，将在计算和药理学专家的监督下，利用蛋白质模型对配体- cb1受体- galphai复合物进行研究。目前的提案将允许获得扎实而广泛的蛋白质建模知识，并将导致具备解决未来生物医学研究领域许多具有挑战性的重要问题的能力。本研究将由Thomas Darden博士（国家环境健康科学研究所结构生物学实验室首席研究员，RTF， NC）作为科学导师和Allyn C. Hewlett博士（神经科学主任）指导。/药物滥用计划，jlc - bri, Durham， NC)作为科学评论员。Brian Thomas（北卡罗来纳州RTP三角研究所化学服务中心主任）和Emad Tajkhorshid（伊利诺伊大学厄巴纳-香槟分校贝克曼研究所理论与计算生物物理小组研究助理主任）为科学顾问成员。该研究的主要目的是通过蛋白质MD模拟方法证明配体可以触发诱导或稳定g蛋白激活所需的受体系列微构象变化。具体目的是：1)构建脑CB1受体与GalphaM复合物的分子模型，包括跨膜螺旋、胞外/胞内环以及缩短的N和c端；2) CB1受体- galphai复合物的蛋白MD模拟；3)通过配体-CB1受体- galphah复合物的蛋白MD模拟将无活性CB1受体转化为活性形式；4)蛋白质MD模拟结果分析。

DESCRIPTION (provided by applicant): This Mentored Research Scientist Development Award (K01) is to develop the research program of Dr. Joong-Youn Shim in the Julius L. Chambers Biomedical/Biotechnology Research Institute (JLC-BBRI) at North Carolina Central University (NCCU). To achieve the scientific goals, protein modeling will be utilized for the study the ligand-CB1 receptor-Galphai complex under the supervision of computational and pharmacology experts. The current proposal will allow to obtain solid and broad knowledge of protein modeling and will lead to be equipped with capability to address many challenging issues important in biomedical research area in the future. This research will be supervised by Dr. Thomas Darden (Principal Investigator, Laboratory of Structural Biology, National Institute of Environmental Health Sciences, RTF, NC) as the scientific mentor and Dr. Allyn C. Hewlett (Director, Neurosci./Drug Abuse Res. Program, JLC-BBRI, Durham, NC) as the scientific comentor, and Drs. Brian Thomas (Director, Center for Chemistry Services, Research Triangle Institute, RTP, NC) and Emad Tajkhorshid (Assistant Director of Research, Theoretical & Computational Biophysics Group, University of Illinois at Urbana-Champaign, Beckman Institute, IL) as the scientific advisory members. The major goal of the proposed research is to demonstrate that the ligand can trigger to induce or stabilize receptor serial micro-conformational changes requisite to G-protein activation by using a protein MD simulations approach. The SPECIFIC AIMS are: 1) Construction of a molecular model, including the transmembrane (TM) helices, the extracellular/ intracellular loops, and the shortened N- and C-terminals of the brain CB1 receptor in complex with GalphaM; 2) Protein MD simulations of the CB1 receptor-Galphai 1 complex; 3) Conversion of the inactive CB1 receptor to its active form by protein MD simulations of the ligand-CB1 receptor-Galphah complex; and 4) Analysis of the protein MD simulation results.