Research Starter Grant

本项目的重点是通过计算机模拟G蛋白偶联受体（gpcr）的构象变化来了解信号转导的分子基础。这些受体参与许多不同的生理功能，如突触神经传递、感觉知觉、通过趋化性吸引运动细胞和有丝分裂的调节。这些也是药物干预极为常见的目标。尽管GPCR信号转导的基本重要性，但缺乏对所涉及的具体构象变化及其背后的物理化学力的详细了解。这主要是由于涉及表达、纯化和结晶这些膜蛋白的实验困难。为了进一步了解GPCR信号转导的分子机制，本项目将首先关注视紫红质，这是表征最好的GPCR，也是唯一一个通过x射线晶体学确定了详细静息状态结构的GPCR。接下来将计算阿片受体的组成活性，然后是孤儿受体ogr1和GPR1对pH变化的响应。计算机模拟应该对受体的激活提供重要的见解。特别是，由于配体结合而导致的小范围、局部结构变化如何传播到更大规模的构象变化，从而使受体能够与G蛋白相互作用。看看这种激活机制是否普遍存在，或者至少对这个庞大而多样的受体家族来说是常见的，这将是一件有趣的事情。本项目开发的方法是通用的，应该广泛适用于其他生物分子系统的大规模模拟，因此将产生更广泛的影响。此外，研究生将参与该项目，并期望进行计算机模拟的某些方面。

The focus of this project is to understand the molecular basis of signal transduction via computer simulations of conformational changes in G protein-coupled receptors (GPCRs). These receptors are involved in many diverse physiological functions such as synaptic neurotransmission, sensory perception, attraction of motile cells by chemotaxis, and regulation of mitosis. These are also extremely common targets for pharmaceutical intervention. Despite the fundamental importance of GPCR signal transduction, a detailed understanding of the specific conformational changes involved and the physical-chemical forces behind them is lacking. This is primarily due to the experimental difficulties involved in expressing, purifying, and crystallizing these membrane proteins. In order to gain further understanding into the molecular mechanisms involving GPCR signaling, this project will focus first on rhodopsin, which is the best characterized GPCR and the only one with a detailed resting state structure determined by X-ray crystallography. This will be followed by calculations of the constitutive activity of opiod receptors, then the response to pH changes by the orphan receptors-OGR1 and GPR1. Computer simulations should provide significant insight into receptor activation. In particular, how small-scale, localized changes in structure due to the binding of a ligand, propagate to the larger-scale conformational changes that enable the receptor to interact with a G protein. It would be interesting to see whether this mechanism of activation is universal or at least common for this large and diverse family of receptors. The methodology to be developed in the course of this project is general and should be widely applicable to large-scale simulations of other biomolecular systems, and thus will have a broader impact. Moreover, graduate students will be involved in this project and are expected to carry out some aspects of the computer simulations.