Mesoscale spatial kinetic modeling of cell systems

细胞系统的中尺度空间动力学建模

基本信息

批准号：
10189659
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
项目类别：
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/10189659
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 Structure 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

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 Structure 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

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项目摘要

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.

该项目的建议是在中尺度开发新的无网络空间建模软件 - 占据详细分子动力学与细胞反应扩散之间的利基市场特别是，我们计划解决50nm - 2µm的空间尺度和临时尺度在100μs到10s的范围内。从中受益的系统示例此“中尺度”的建模工具是接收器信号平台和簇（例如免疫突触或突触后密度），细胞粘合剂复合物，脂质筏，染色质组织，细胞骨架动力学和核蛋白相。我们的方法建立在 Springsalad软件的基础，该软件使用Langevin动力学形式进行建模具有明确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，例如聚类和聚合。方法是动力学和分子建模的汞合金，因为它从两者中得出了反应的可能性分子和宏观生化参数的粗糙结构特征，例如开关率常数，差异系数和变构状态过渡速率。现在 Springsalad表示分子是线性接头连接的球形“位点”，被建模为僵硬的弹簧。分子可以在矩形体积中扩散并反应或锚定在膜的平面斑块。我们的具体目的是大幅度扩大的范围 Springsalad通过允许对结构细节的更现实表示并扩展可以建模的生物物理机制范围。更好地说明聚类上的膜曲率和跨越薄薄的组件的可能性诸如丝状或内吞作用之类的过程，我们将实施布朗尼的方法沿弯曲机制的动力学。我们将开发方法来得出来自更现实的3D分子数据（包括原子坐标）的球形位点和接头。我们将开发新的可选方案，以更好地说明分子结构的刚性在这个粗粒的水平上，分别是接头域的灵活性；后来会帮助我们代表本质上无序的域的影响。我们将发展统计和分析方法来分析模拟结果并构建集团模型，以便从这个中尺度到整个细胞尺度。最后，我们建议通过考虑到现场经历的当地力量，并适当改变了可能性解开（即关闭率），结合（率）和膜表面的张力。最终， Springsalad功能将纳入虚拟小区软件系统中。