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

项目摘要 细胞表面上的膜受体占批准的药物靶点的60%左右。 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如粘附和凋亡的基础。 最近的研究进一步表明，受体结合的特异性可以通过合成 人工将分子配体的不同亚基缀合在一起的嵌合配体。这提供了 这是一个有前途的策略，以提高基于药物的治疗的效率和选择性。但我们的 对膜受体的细胞功能的理解在很大程度上受到以下事实的限制： 仅在极少数情况下成功地测量了受体的结合。最 方法将受体和配体从它们的生物环境中分离， 方便分析。在活细胞中，受体锚定在质膜表面。的 膜限制显著影响受体的结合动力学。此外，绑定还可以 由嵌合配体的柔性和多价性调节。这些多层次的复杂性导致了 难以定量细胞表面上膜受体的结合动力学。计算建模 可以达到目前实验室无法达到的尺寸。因此，这一目标 建议建立不同尺度下的细胞表面结合动力学模型 受体及其胞外蛋白配体。我们开发了不同的方法来模拟 分子和低分辨率水平上的蛋白质结合动力学。通过应用这些 T细胞和共刺激受体特异性检测体系的建立， 正在进行的实验合作，我们特别有兴趣回答以下两个问题 问题：膜限制如何影响受体和配体之间的结合，以及 是多价配体在调节受体结合中的功能作用。使用信息 基于这两方面的研究，我们将进一步构建一个多尺度的建模框架 为了定量计算多价配体和多个受体之间的结合动力学， 在细胞表面。我们的长期目标是实际设计用于特定膜的多价配体 受体，这样就可以人工调节细胞信号。总之，这项研究将揭示 配体-受体相互作用的基本机制和新药候选物的设计原则。 此外，多尺度模型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.