A multiscale model for binding kinetics of membrane receptors on cell surfaces

项目摘要 细胞表面的膜受体约占已批准的药物靶点的60% 医药市场。在大多数情况下，它们与细胞外配体结合，并启动各种细胞内 信号通路。这一过程是许多细胞活动的基础，如黏附和细胞凋亡。 最近的研究进一步表明，受体结合的特异性可以通过合成 人工地将分子配体的不同亚基结合在一起的嵌合配体。这提供了一种 提高药物治疗的效率和选择性的有希望的战略。然而，我们的 对膜受体的细胞功能的了解在很大程度上受到以下事实的限制：在体内 只有极少数情况下才能成功地测量到受体的结合。多数 方法将受体和配体从生物环境中分离出来，以允许更多的 分析方便。在活细胞中，受体固定在质膜表面。这个 膜限制显著影响受体的结合动力学。此外，绑定也可以是 受嵌合配体的灵活性和多价性调节。这些多层次的复杂性导致了 难以量化细胞表面膜受体的结合动力学。计算建模 可以达到目前在实验室中无法达到的尺寸。因此，这一行动的目标是 建议建立不同尺度的综合模型来研究细胞表面的结合动力学 受体及其胞外蛋白配体。我们已经开发了不同的方法来模拟 蛋白质在分子和低分辨率水平上的结合动力学。通过应用这些 方法建立T细胞和共刺激受体的特异性检测体系，建立 正在进行的实验性合作，我们特别感兴趣的是回答以下两个问题 问题：膜限制如何影响受体和配体之间的结合，以及什么 是多价配体在调节受体结合中的功能作用。使用这些信息 基于这两个方面的研究，我们将进一步构建一个多尺度的建模框架 定量计算多价配体与多受体的结合动力学 在细胞表面。我们的长期目标是为特定的膜设计实用的多价配体 受体，以便细胞信号可以被人为地调节。综上所述，这项研究将有助于 配体-受体相互作用的基本机制和新药候选的设计原则。 此外，该多尺度模型还可以应用于特定的膜受体系统。

Project Summary Membrane receptors on cell surfaces constitute around 60% of approved drug targets on the pharmaceutical market. In most cases, they bind to extracellular ligands and initiate various intracellular signaling pathways.  This process underlies many cellular activities such as adhesion and apoptosis. Recent studies further showed that specificity of receptors binding can be modulated by synthesizing chimeric ligands that artificially conjugate different subunits of molecular ligands together. This provides a promising strategy to improve the efficiency and selectivity of drug-based therapies. However, our understanding to the cellular functions of membrane receptors is largely limited by the fact that in vivo binding of receptors has only been successfully measured in a very small number of cases. Most methods isolate receptors and ligands from their biological surrounding in order to permit a more convenient analysis. In living cells, receptors are anchored on surfaces of plasma membrane. The membrane confinement significantly affects binding kinetics of receptors. Moreover, binding can also be regulated by the flexibility and multivalency of chimeric ligands. These multi-level complexities lead to the difficulty in quantifying binding kinetics of membrane receptors on cell surfaces. Computational modeling can reach dimensions that are currently unapproachable in the laboratory. Thus, the objective of this proposal is to build integrative models at different scales for studying the binding kinetics of cell surface receptors with their extracellular protein ligands. We have developed different methods for simulating protein binding kinetics on the molecular and lower-resolution levels. Through the application of these methods to specific testing systems of T cell and costimulatory receptors, and the establishment of ongoing experimental collaborations, we are specifically interested in answering the following two questions: how does membrane confinement affect binding between receptors and ligands, and what are the functional roles of multivalent ligands in regulating receptor binding. Using the information derived from these two aspects of studies, we will further construct a multiscale modeling framework to quantitatively calculate the kinetics of binding between multivalent ligands and multiple receptors on cell surfaces. Our long-term goal is to practically design multivalent ligands for specific membrane receptors so that cell signaling can be artificially modulated. In summary, this study will sheds light on both basic mechanisms of ligand-receptor interactions and design principles of new drug candidates. Moreover, the multiscale model can be applied to specific membrane receptor systems.