DISTINCTIVE RECEPTOR ACTIONS IN HALLUCINOGEN MECHANISMS

PPG的这一部分致力于定量、结构和计算建模 我们的合作努力，以了解致幻药物在各种机制方面， 结构类，由它们与5-HT GPCR亚型的相互作用触发。的目的 了解产生幻觉的复杂行为效应的机制， 基于这样的假设，即某些化合物的致幻潜力是由特定的 与这些受体的相互作用模式，产生不同的分子信号传导机制; 因此，致幻剂触发结构和动态受体反应（影响蛋白质-蛋白质 相互作用），其不同于由其他配体产生的那些。这一假设导致提出 研究（i）受体反应的模式（构象重排和 稳定“活化状态”），其触发特殊的蛋白质-蛋白质相互作用， 受体寡聚化与各种支架蛋白相互作用（例如，PDZ-BAR-结构域）， 以及（ii）这种构象重排和由此产生的蛋白质- 蛋白质相互作用影响致幻剂信号通路的选择性和效率。我们 开发和应用计算方法，建模和模拟方法（从结构 生物物理学，生物信息学，预测数学建模）来研究分子和细胞 参与机制的信号系统。这些研究与项目2密切协调 和PPG的3个，其中模型的探测和验证将基于协作 设计的实验，利用推理，设计和蛋白质构建体研究，在这个 项目这些合作研究将有助于将分子的结构背景 致幻剂信号机制的系统水平模型中的相互作用。的组件 致幻剂信号图将被存储在信息管理系统（SigPath）中 最终用于对途径进行定量建模并了解其特征性质， 以及它们在细胞机制中的整合。我们计划从适度的科学的 负责任地模拟小途径元素，以支持假设检验， 设计PPG中探索此类途径的实验。

This component of the PPG is dedicated to quantitative, structural, and computational modeling aspects of our collaborative effort to understand the mechanisms of hallucinogenic drugs in various tructural classes, triggered by their interactions with the subtypes of 5-HT GPCRs. The aim to understand the mechanisms that engender the complex behavioral effects in hallucinogenesis, is based on the hypothesis that the hallucinogenic potential of certain compounds results from specific modes of interaction with these receptors, that produce distinct molecular signaling mechanisms; thus, hallucinogens trigger structural and dynamic receptor responses (affecting protein-protein interactions) that differ from those produced by other ligands. This hypothesis leads to proposed investigations of (i) the modes of receptor response (conformational rearrangements and stabilization of "activated state(s)") that trigger special protein-protein interactions ranging from receptor oligomerization to interactions with various scaffolding proteins (e.g., PDZ- BAR-domains), and (ii) how such conformational rearrangements and resulting association/dissociation of protein- protein interactions affect selectivity and efficiency in the signaling pathways of hallucinogens. We develop and apply computational methods, modeling and simulation approaches (from structural biophysics, bioinformatics, predictive mathematical modeling) to study molecular and cellular signaling systems involved in the mechanisms. The studies are closely coordinated with Projects 2 and 3 of the PPG in which probing and validation of the models will be based on collaboratively designed experiments utilizing inferences, designs and protein constructs investigated in this project. These collaborative studies will serve to incorporate the structural context of molecular interactions in systems level models of the hallucinogen signaling mechanisms. The components of a hallucinogen signaling map will be stored in an information management system (SigPath) ultimately used to model quantitatively the pathways and learn about their characteristic properties, and their integration in the cellular machinery. We plan to start with modest, scientifically responsible simulations of small pathway elements in order to support hypothesis testing and design of experiments in the PPG that explore such pathways.