The CB1 Cannabinoid Receptor Activation By Protein Molecular Dynamics Simulations

描述（由申请人提供）：这个指导研究科学家发展奖（K 01）是为了发展博士的研究项目。北卡罗来纳州中央大学（NCCU）的钱伯斯生物医学/生物技术研究所（JLC-BBRI）。为了实现科学目标，蛋白质建模将在计算和药理学专家的监督下用于研究配体-CB 1受体-Galphai复合物。目前的建议将允许获得蛋白质建模的坚实和广泛的知识，并将导致配备能力，以解决许多具有挑战性的重要问题，在未来的生物医学研究领域。本研究将由托马斯达登博士（主要研究员，结构生物学实验室，国家环境健康科学研究所，RTF，NC）作为科学导师和Allyn C. Hewlett（主任，神经科学/药物滥用研究计划，JLC-BBRI，达勒姆，NC）作为科学评论员，Brian托马斯博士（主任，化学服务中心，三角研究所，RTP，NC）和Emad Tajkhorshid（研究助理主任，理论和计算生物物理组，伊利诺伊大学厄巴纳-香槟分校，贝克曼研究所，IL）作为科学顾问成员。该研究的主要目标是通过蛋白质分子动力学模拟方法证明配体可以触发诱导或稳定G蛋白活化所需的受体系列微观构象变化。具体目标是：1）构建分子模型，包括与GalphaM复合的脑CB 1受体的跨膜（TM）螺旋、细胞外/细胞内环和缩短的N-和C-末端; 2）CB 1受体-Galpha 1复合物的蛋白质MD模拟; 3）通过配体-CB 1受体-Galpha 1复合物的蛋白质MD模拟将失活CB 1受体转化为其活性形式; 4）蛋白质分子动力学模拟结果分析。

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.