Approaches to Modeling Key Elements in Glutamate Receptors Activation Mechanism

描述（由申请人提供）：离子型谷氨酸受体是一种膜蛋白，负责启动大多数神经细胞之间的兴奋性传递。这些重要的神经递质受体的激活涉及许多神经退行性疾病，包括中风和癫痫。此外，增强谷氨酸受体AMPA亚型谷氨酸活性的药物（变构调节剂）已被证明可以改善认知，并可能对阿尔茨海默病等神经退行性疾病有益。NMDA型谷氨酸受体在长时程增强中起重要作用，而长时程增强对学习和记忆有重要作用。由于谷氨酸受体的重要性，近十年来，人们对谷氨酸受体的结构、组织和功能机制进行了大量的研究。最近发表了AMPA型GluA2受体的第一个完整受体结构。然而，我们还远未完全了解这些受体的功能，特别是在定量水平上。该建议旨在开发配体结合结构域二聚体和跨膜结构域的不同构象状态的自由能差异的假设但定量模型，这将有助于进一步完善功能模型，我们对该通道功能机制的理解，并通过产生可检验的假设和模型或在更高分辨率下进一步完善来帮助进一步的实验和理论工作。我们将使用计算化学的方法：分子动力学模拟和连续静电计算配体结合和跨膜结构域的不同构象状态的自由能，并比较不同蛋白质亚型、突变体和配体存在或不存在时相对自由能的差异。这将使我们能够在定量水平上破译受体的功能机制，并最终实现这些蛋白质的详细分子模型，这些蛋白质将具有预测能力，并将在例如合理的药物设计中变得有用。 在正常浓度下，谷氨酸对大脑功能如学习和记忆至关重要。但是当神经元受损时，谷氨酸会大量涌出，在附近的神经元之间积聚，并通过过度兴奋杀死它们。这个建议是针对了解门控谷氨酸受体离子通道结合后的配体谷氨酸。这是一个理论研究。一旦这些模型被开发出来，并与现有的实验数据进行了比较，那么借助计算机进行合理的药物设计将降低新药开发的成本，缩短新药开发的时间。

DESCRIPTION (provided by applicant): Ionotropic Glutamate receptors are membrane proteins that are responsible for initiation of excitatory transmission between most neural cells. Activation of these important neurotransmitter receptors is involved in a number of neurodegenerative diseases, including stroke and epilepsy. In addition, drugs that enhance the activity of glutamate at the AMPA subtype of glutamate receptors (allosteric modulators) have been shown to improve cognition and may have benefits in neurodegenerative diseases such as Alzheimer's disease. NMDA type glutamate receptors are important for long term potentiating, which is important to learning and memory. Due to their importance therefore much work has been put in recent decade into research to characterize glutamate receptors structural organization and functional mechanisms. The first full receptor structure of the AMPA type GluA2 receptor has recently been published. Yet, we are far from complete understanding of how these receptors function, especially at the quantitative level. This proposal seeks to develop hypothetical yet quantitative models of the free energy differences of different conformational states of the ligand binding domain dimers and the transmembrane domain that will aid further refinement of functional model, our understanding of mechanism of this channel functioning and in aiding further experimental and theoretical work by producing testable hypotheses and models or further refinement at the higher resolution. We will use methods of computational chemistry: molecular dynamics simulations and continuum electrostatics to compute free energies of distinct conformational states of the ligand binding and transmembrane domains and compare, how differences in relative free energies change for different protein sub-types, mutants and in the presence or absence of the ligands. This will allow us to decipher the functional mechanisms of the receptor at the quantitative level and eventually achieve detailed molecular models of such proteins that will have predictive power and will become useful in, e.g. rational drug design. PUBLIC HEALTH RELEVANCE: At normal concentrations, glutamate is crucial for brain functions such as learning and memory. But when neurons are damaged, glutamate pours out, builds up between nearby neurons, and kills them by overexciting them. This proposal is targeted toward understanding gating of the glutamate receptor ion channel upon binding of the ligand glutamate. This is a theoretical study. Once the models are developed and tested against available experimental data - rational drug design with the aid of the computers will lower the costs and shorten the time of the new drug development.