MOLECULAR DYNAMICS SIMULATION OF GPCR CB2 RECEPTOR IN LIPID BILAYERS AND QUANTU

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 大麻(或大麻素，CB)受体被归类为视紫红质样G蛋白偶联受体(GPCRs)家族的成员，该家族约占全球现有药物的45%。事实上，由于膜蛋白的固有性质，由于缺乏适合于X射线结晶学研究的高质量晶体或用于核磁共振研究的统一同位素标记的天然蛋白质，因此很少有人报道任何GPCR的高分辨率结构。最重要的是，事实证明，非常有限的蛋白质表达系统在功能状态下产生全长GPCR是令人满意的，并且具有足够的产量用于生物物理研究。 本研究的目的是进一步发展和改进我们建立的CB2膜蛋白(MP)结构生物学方法，然后应用这些结构和功能参数来精炼同源生成的三维CB2结构模型。长期目标是通过了解与CB2受体相关的结构和功能事件，为合理的CB2配体设计开发CB2受体结构模型。具体地说，我们将针对以下目标： 目的：1.MD模拟以完善预测的3DGPCRCB2受体结构模型(初步工作已完成，已发表两篇论文)。 目的：进一步用分子动力学方法计算膜模型中的3DCB2受体结构(使用GROMACS对脂/水模拟双层膜体系中的CB2受体进行分子动力学模拟)。如此大型的生物系统需要高功率的计算设施，可用@PSC。 目的：开展受体对接研究，探索活性配体结合构象，并利用QM方法进一步评估结合能，包括。 用于从头计算的高斯 所完成的工作有望对大麻素的研究，特别是对GPCR核磁共振结构生物学的研究做出宝贵的贡献。提出的这项工作的潜在意义是，它将极大地有助于我们设计仅作用于大麻素CB2受体的免疫调节药物。这些药物可能是治疗自身免疫性疾病和免疫性疾病的潜在药物，如多发性硬化症、狼疮和神经炎性疼痛等。

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. The marijuana (or cannabinoid, CB) receptors are classified as members of rhodopsin-like G-protein coupled receptors (GPCRs) family that represents ~45% of current drugs worldwide. In fact, due to the intrinsic properties of membrane proteins, very few high-resolution structures have been reported for any GPCRs due to the lack of high-quality crystals suitable for X-ray crystallography studies, or uniformly isotope-labeled "native" proteins for NMR studies. The most important is due to the fact that very limited protein expression systems have proven satisfactory for producing the full-length GPCRs in a functional state and with sufficient yields for biophysical studies. The objective of this research to further develop and improve our established CB2 membrane protein (MP) structural biology approaches, and then applies these structural and functional parameters to refine the homology-generated 3D CB2 structure model. The long range goal is to develop the CB2 receptor structure model for rational CB2 ligand design via understanding of the structural and functional events associated with CB2 receptor. Specifically, we will target the following aims: Aim1. MD simulations to refine the predicted 3D GPCR CB2 receptor structure models (preliminary work completed with two publications). Aim2: Further molecular dynamics (MD) calculations of the 3D CB2 receptor structure in membrane model (using GROMACS for MD simulation of the CB2 receptor in the lipid/water simulated bilayer membrane system. Such a large biosystem requires high power computing facility that is available @PSC. Aim3: Carry out receptor docking studies to explore the active ligand binding conformations and further evaluate the binding energy using QM approaches, including. GAUSSIAN for ab initio computations The accomplished work is expected to make a valuable contribution to cannabinoid research in particular and GPCR NMR structural biology in general. The potential significance of the work proposed is that it would contribute greatly to our ability to design immunomodulatory drugs that act solely at the cannabinoid CB2 receptor. These drugs could be potential therapeutic agents for autoimmune diseases and immunological disorders such as Multiple Sclerosis, Lupus, and neuroinflammatory pains, etc.