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

细胞表面膜受体结合动力学的多尺度模型

• 批准号: 9156383
• 负责人: Yinghao Wu
• 金额: $ 32.98万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE, INC
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9156383
• 关键词: Adhesions; Affect; Algorithms; Apoptosis; Binding; Binding Proteins; Binding Sites; Biological; Cell Surface Receptors; Cell membrane; Cell physiology; Cell surface; Cells; Cereals; Collaborations; Computer Simulation; Computing Methodologies; Diffusion; Dimensions; Drug Design; Drug Targeting; Endocytosis; Environment; Extracellular Protein; Goals; In Vitro; Kinetics; Knowledge; Label; Laboratories; Lead; Life; Ligand Binding; Ligands; Light; Marketing; Measures; Membrane; Methods; Microscopic; Modeling; Molecular; Nature; Pharmaceutical Preparations; Pharmacologic Substance; Physics; Plasma; Play; Process; Proteins; Public Health; Receptor Cell; Resolution; Role; Signal Pathway; Signal Transduction; Specificity; Surface; System; T-Lymphocyte; Testing; Validation; Work; base; design; drug candidate; extracellular; flexibility; improved; in vivo; interest; multi-scale modeling; novel therapeutics; plasmonics; receptor; receptor binding; research study; simulation

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.

项目摘要 细胞表面上的膜受体约占批准的药物靶标的60％ 制药市场。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。这个过程是许多细胞活性的基础，例如粘合剂和凋亡。 最近的研究进一步表明，可以通过合成来调节受体结合的特异性 嵌合体配体，将分子配体的不同亚基共轭在一起。这提供了 提高基于药物疗法的效率和选择性的有希望的策略。但是，我们的 对膜受体的细胞功能的理解在很大程度上受体内的事实限制 接收器的结合仅在非常少量的情况下才能成功测量。最多 方法将受体和配体与它们的生物周围隔离，以便更多 方便的分析。在活细胞中，受体锚定在质膜的表面上。这 膜限制显着影响受体的结合动力学。而且，约束也可以是 受嵌合配体的柔韧性和多价性调节。这些多层复杂性导致 量化细胞表面上膜受体的结合动力学的难度。计算建模 可以达到实验室目前无法接近的尺寸。那是这个目标 建议是在不同尺度上构建集成模型，以研究细胞表面的结合动力学 带有细胞外蛋白质配体的接收器。我们开发了模拟的不同方法 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细胞和共刺激受体的特定测试系统的方法，并建立 正在进行的实验合作，我们特别有兴趣回答以下两个 问题：膜限制如何影响受体和配体之间的结合，以及什么 是多价配体在控制受体结合中的功能作用。使用信息 从研究的这两个方面得出，我们将进一步构建一个多尺度建模框架 定量计算多价配体和多个接收器之间结合的动力学 在细胞表面上。我们的长期目标是实际设计用于特定膜的多价配体 受体，可以人为地调节细胞信号。总而言之，这项研究将阐明 配体 - 受体相互作用的两种基本机制和新药候选人的设计原理。 此外，多尺度模型可以应用于特定的膜受体系统。