Approaches to Modeling Key Elements in Glutamate Receptors Activation Mechanism

谷氨酸受体激活机制关键元件的建模方法

基本信息

批准号：
8321974
负责人：
MARIA G KURNIKOVA
金额：
$ 19.08万
依托单位：
CARNEGIE-MELLON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-01 至 2014-03-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8321974
关键词：
Address Agonist Allosteric Regulation Alzheimer&apos s Disease Binding Biophysics Brain Cereals Cognition Collaborations Comprehension Computer Assisted Computer software Data Drug Design Electrostatics Elements Ensure Environment Epilepsy Equilibrium Free Energy Glutamate Receptor Glutamates Goals Hydrophobicity Indium Individual Ion Channel Knowledge Lead Learning Letters Ligand Binding Ligand Binding Domain Ligands Lipids Medicine Membrane Proteins Memory Methods Modeling Molecular Molecular Conformation Molecular Models N-Methylaspartate Neurodegenerative Disorders Neurons Neurotransmitter Receptor Outcome Outcomes Research Paper Pharmaceutical Preparations Positioning Attribute Probability Property Proteins Publishing Receptor Activation Relative (related person)Research Research Personnel Resolution Resources Rest Sampling Stroke Structure System Testing Theoretical Studies Theoretical model Time Transmembrane Domain Work computational chemistry conformational conversion cost design dimer drug development improved killings molecular dynamics molecular modeling monomer mutant protein complex receptor receptor function research study simulation theories transmission process two-dimensional water solution

项目摘要

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.

描述（由申请人提供）：离子型谷氨酸受体是膜蛋白，负责大多数神经细胞之间的兴奋性传播。这些重要的神经递质受体的激活参与了许多神经退行性疾病，包括中风和癫痫。此外，已经证明，增强谷氨酸在AMPA亚型（变构调节剂）AMPA亚型的活性的药物已被证明可以改善认知，并可能在神经退行性疾病（例如阿尔茨海默氏病）中受益。 NMDA型谷氨酸受体对于长期增强非常重要，这对于学习和记忆很重要。由于它们的重要性，因此在最近的十年中，已经进行了许多工作，以表征谷氨酸受体结构组织和功能机制。 AMPA型GLUA2受体的第一个完整受体结构最近发表了。但是，我们远没有完全理解这些受体的功能，尤其是在定量水平上。该提案旨在开发假设但定量的模型，以实现配体结合结构域二聚体不同构象状态的自由能差和跨膜结构域的自由能差，这些模型将有助于进一步完善功能模型，我们对该通道功能的机制的理解，以及通过进一步的实验性和理论工作来实现实验性和理论性工作，从而有助于实验和理论进行可检识的假设和模型，或进一步改进或进一步进行介绍。我们将使用计算化学方法的方法：分子动力学模拟和连续静电仪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，突变体的相对自由能的差异如何变化。这将使我们能够在定量水平上破译受体的功能机制，并最终获得此类蛋白质的详细分子模型，这些蛋白具有预测能力并将在例如理性药物设计。