Mesoscale spatial kinetic modeling of cell systems

细胞系统的中尺度空间动力学建模

• 批准号: 10437690
• 负责人: LESLIE M LOEW
• 金额: $ 34.44万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-20 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10437690
• 关键词: 3-Dimensional; Accounting; Address; Amalgam; Binding; Binding Sites; Biochemical; Biological Models; Biophysical Process; Cell Adhesion; Cell model; Cell physiology; Cells; Chromatin; Code; Complex; Computer Models; Computer software; Data; Diabetes Mellitus; Diffuse; Diffusion; Disease; Filopodia; Foundations; Geometry; Grain; Grant; Java; Kidney Failure; Kinetics; Malignant Neoplasms; Membrane; Membrane Microdomains; Methods; Modeling; Molecular; Molecular Structure; Nucleoproteins; Performance; Phase; Probability; Process; Reaction; Receptor Signaling; Running; Scheme; Shapes; Signal Transduction; Site; Specific qualifier value; Speed; Statistical Data Interpretation; Statistical Methods; Surface; Synapses; System; Technology; Thinness; analytical method; autism spectrum disorder; base; combinatorial; density; experience; flexibility; immunological synapse; improved; insight; kinetic model; mechanical force; models and simulation; molecular dynamics; molecular modeling; novel strategies; particle; polymerization; reaction rate; simulation; software systems; stoichiometry; tool; vector; virtual

This project proposes to develop new network-free spatial modeling software at the mesoscale - occupying the niche between detailed molecular dynamics and cellular reaction-diffusion systems. Specifically, we plan to address spatial scales in the range of 50nm – 2µm and temporal scales within the range of 100µs to 10s. Examples of systems that would benefit from modeling tools at this “mesoscale” are receptor signaling platforms and clusters (e.g. the immune synapse or the post-synaptic density), cell adhesion complexes, lipid rafts, chromatin organization, cytoskeletal dynamics, and nucleoprotein phases. Our approach builds on the foundation of the SpringSaLaD software, which uses a Langevin dynamics formalism to model multi-molecular interactions with explicit excluded volumes. It permits spatial simulations of combinatorially complex processes such as clustering and polymerization. The approach is an amalgam of kinetic and molecular modeling, in that it derives probabilities of reactions from both coarse structural features of the molecules and macroscopic biochemical parameters such as on and off rate constants, diffusion coefficients and allosteric state transition rates. Currently SpringSaLaD represents molecules as spherical “sites” connected by linear linkers, modeled as stiff springs. Molecules can diffuse and react either in a rectangular volume or be anchored to a planar patch of membrane. Our Specific Aims propose to dramatically expand the scope of SpringSaLaD by allowing more realistic representation of structural details and expanding the range of biophysical mechanisms that can be modelled. To better account for the influence of membrane curvature on clustering and the possibility of assemblies that span across thin processes such as filopodia or endocytic invaginations, we will implement methods for Brownian dynamics along curved membranes. We will develop methods to derive the arrangement of spherical sites and linkers from more realistic 3D molecular data, including atomic coordinates. We will develop new optional schemes to better account for the rigidity of molecular structures at this coarse-grained level and, separately, the flexibility of linker domains; the latter will help us represent the influence of intrinsically disordered domains. We will develop statistical and analytical methods to analyze simulation results and build lumped models so as to bridge from this mesoscale to the full cell scale. Finally, we propose to support mechanochemistry by accounting for local force experienced by a site and appropriately altering probabilities for unbinding (i.e. off rates), binding (on-rates) and the tension at membrane surfaces. Ultimately, the SpringSaLaD functionality will be incorporated within the Virtual Cell software system.

本项目建议开发新的中尺度无网络空间模拟软件-- 在详细分子动力学和细胞反应扩散之间占据一席之地 系统。具体地说，我们计划解决50 nm-2微米范围内的空间尺度和 时间刻度范围为100微米S至10秒。受益于以下项目的系统示例 这个“中尺度”的建模工具是受体信号平台和集群(例如 免疫突触或突触后密度)、细胞黏附复合体、脂筏、染色质 组织、细胞骨架动力学和核蛋白阶段。我们的方法建立在 SpringSaLaD软件的基础，该软件使用朗之万动力学形式来建模 显式排除体积的多分子相互作用。它允许空间模拟 组合复杂的过程，如集群和聚合。这种方法是一种 动力学和分子模拟的混合体，因为它从两者中推导出反应的概率 分子的粗略结构特征和宏观生化参数，如 开和关速率常数，扩散系数和变构状态转换率。目前 SpringSaLaD将分子表示为由线性链接器连接的球形“位置”，模型为 僵硬的弹簧。分子可以在矩形体积内扩散和反应，也可以固定在 平面膜贴片。我们的具体目标是大幅扩大 SpringSaLaD通过允许更逼真地表示结构细节并扩展 可以模拟的生物物理机制的范围。为了更好地解释 成团的膜曲率和跨越薄层的组件的可能性 进程，如丝状足或内吞内陷，我们将实现方法的布朗 沿着弯曲的膜的动力学。我们将开发方法来推导出 来自更真实的3D分子数据的球形位置和连接子，包括原子坐标。 我们将开发新的可选方案，以更好地解释分子结构的刚性 在这个粗粒度级别，以及链接器域的灵活性；后者将帮助我们 表示本质上无序的区域的影响。我们将发展统计和 分析模拟结果并建立集总模型的分析方法，以便从 从这个中尺度到完整的细胞尺度。最后，我们建议通过以下方式支持机械力化学 考虑到场地所经历的局部力，并适当改变 解除结合(即关闭速率)、结合(开启速率)和膜表面的张力。最终， SpringSaLaD功能将并入虚拟细胞软件系统。