The CB1 Cannabinoid Receptor Activation By Protein Molecular Dynamics Simulations

描述(由申请者提供)：本指导研究科学家发展奖(K01)是为了发展Shim博士在北卡罗来纳中央大学Julius L.Chambers生物医学/生物技术研究所(JLC-BBRI)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，利用蛋白质建模来研究配体-CB1受体-Galphai复合体。目前的提议将允许获得坚实和广泛的蛋白质建模知识，并将使其有能力解决未来生物医学研究领域中许多具有挑战性的重要问题。这项研究将由Thomas Darden博士(北卡罗来纳州RTF国家环境健康科学研究所结构生物学实验室首席研究员)担任科学导师，Allyn C.Hewlett博士(JLC-BBRI神经科学/药物滥用研究项目主任，北卡罗来纳州达勒姆市)担任科学顾问，Brian Thomas博士(北卡罗来纳州RTP研究三角研究所化学服务中心主任)和Emad Tajkhorshid博士(伊利诺伊州伊利诺伊大学厄巴纳-香槟分校研究、理论和计算生物物理学小组助理主任)担任科学咨询成员。这项研究的主要目的是通过蛋白质分子动力学模拟的方法，证明配体可以触发诱导或稳定G蛋白激活所需的受体一系列微构象变化。具体目标是：1)构建分子模型，包括脑CB1受体与GalphaM复合物的跨膜螺旋、细胞外/细胞内环以及缩短的N末端和C末端；2)蛋白质MD模拟CB1受体-Galphai 1复合体；3)通过对配体-CB1受体-Galphah复合体的蛋白质MD模拟将失活的CB1受体转换为活性形式；以及4)分析蛋白质MD模拟结果。

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.