Single Molecular Receptor Dynamics

神经信号在身体和大脑中的传递依赖于一种叫做受体的蛋白质。大多数控制记忆和学习的神经传递是由嗜离子性谷氨酸受体控制的，所谓的嗜离子性谷氨酸受体，是因为在谷氨酸（神经递质）结合后，它们在神经元上打开一个孔，允许带正电荷的离子（钠和钾）通过。这是大脑中所有神经信号的基础。因此，谷氨酸受体与从癫痫到阿尔茨海默病等中枢神经系统（CNS）的许多神经系统疾病有关，这也许不足为奇。尽管取得了许多进展，但受体与谷氨酸结合时如何改变构象（形状）仍不清楚。在我们之前的工作中，我们能够证明，对于一个叫做盐酸盐受体的特殊亚家族，远离谷氨酸结合位点的区域如何控制受体的动态特性。特别是，这个区域含有钠离子和氯离子的单独结合位点。我们之前的工作表明，将我们在计算生物化学方面的专业知识与加拿大同事的实验专业知识相结合的合作方法在理解这些受体的工作方式方面非常有效。在这个提议中，我们想把我们在盐酸盐受体上学到的知识应用到另一个主要的嗜离子性谷氨酸受体亚家族，AMPA受体。这项工作的重点是了解受体内关键界面的组成如何控制受体可以访问的构象。从长远来看，我们在这里获得的知识对于设计针对神经系统疾病的新化合物非常有用。我们的建议利用分子模拟的力量来提供控制这种结合位点行为方式的原子级细节。如果我们要有机会开发出以可预测的方式起作用的化合物，就必须充分了解这一点。我们将产生的结果将由加拿大麦吉尔大学和丹麦哥本哈根大学的合作者进行验证和测试。

The transmission of nerve signals in the body and brain is dependent on proteins called receptors. Most neurotransmission that governs memory and learning is controlled by ionotropic glutamate receptors, so-called, because upon binding of glutamate (the neurotransmitter) they open a pore into the neuron that allows positively charged ions (sodium and potassium) to pass through it. This is the basis of all nerve signals in the brain. It is therefore perhaps unsurprising that glutamate receptors have been implicated in many neurological conditions of the central nervous system (CNS) ranging from epilepsy to Alzheimer's disease. Despite much progress, exactly how the receptor changes conformation (shape) when it binds glutamate sill remains unclear.In our previous work, we were able to show, for one particular sub-family of receptors called kainate receptors, how a region away from the glutamate-binding site could control the dynamic properties of the receptor. In particular, this region contains separate binding sites for sodium and chloride ions. Our previous work demonstrated that a collaborative approach which combined our expertize in computational biochemistry with experimental expertize of colleagues in Canada was extremely powerful in understanding the way in which these receptors work.In this proposal we want to apply what we have learnt on the kainate receptors to another major subfamily of ionotropic glutamate receptors, the AMPA receptors. The work focuses on understanding how the composition of a key interface within the receptor controls which conformations the receptor can access. The knowledge we gain here, can in the longer-term be very useful for the design of new compounds that target neurological diseases.Our proposal utilizes the power of molecular simulations to provide atomic-level detail of what controls the way this binding site behaves. A full understanding of this is necessary if we are to have any chance of developing compounds that act in a predictable way. The results we will generate will be verified and tested by our collaborators at McGill University, Canada and also at the University of Copenhagen, Denmark.