Approaches to Modeling Key Elements in Glutamate Receptors Activation Mechanism

描述（由申请人提供）：嗜离子性谷氨酸受体是一种膜蛋白，负责大多数神经细胞之间兴奋性传递的启动。这些重要的神经递质受体的激活与许多神经退行性疾病有关，包括中风和癫痫。此外，增强谷氨酸受体AMPA亚型（变构调节剂）谷氨酸活性的药物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型谷氨酸受体对长时程增强很重要，对学习和记忆很重要。由于其重要性，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深入的研究。最近首次发表了AMPA型GluA2受体的完整受体结构。然而，我们对这些受体的功能还远远没有完全了解，特别是在定量水平上。本提案旨在建立配体结合域二聚体和跨膜域不同构象状态的自由能差的假设定量模型，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，并通过产生可测试的假设和模型或在更高分辨率上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来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是如何变化的。这将使我们能够在定量水平上破译受体的功能机制，并最终获得这些蛋白质的详细分子模型，这些模型将具有预测能力，并将在合理的药物设计中发挥作用。

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.