Mesoscale spatial kinetic modeling of cell systems

该项目建议开发新的中尺度无网络空间建模软件 - 占据详细分子动力学和细胞反应扩散之间的利基 系统。具体来说，我们计划解决 50nm – 2μm 范围内的空间尺度， 时间尺度在 100μs 到 10s 范围内。受益于的系统示例 这种“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）、细胞粘附复合物、脂筏、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 动力学形式主义进行建模 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。该方法是一个 动力学和分子模型的混合体，因为它从两者中得出反应的概率 分子的粗略结构特征和宏观生化参数，例如 开关速率常数、扩散系数和变构状态转变速率。目前 SpringSaLaD 将分子表示为由线性连接器连接的球形“位点”，建模为 僵硬的弹簧。分子可以在矩形体积中扩散和反应，也可以锚定在 平面膜片。我们的具体目标建议大幅扩大 SpringSaLaD 通过允许更真实地表示结构细节并扩展 一系列可以建模的生物物理机制。为了更好地考虑影响 膜曲率对聚类的影响以及跨薄层组装的可能性 丝状伪足或内吞内陷等过程，我们将实现布朗运动的方法 沿弯曲膜的动力学。我们将开发方法来导出排列 来自更真实的 3D 分子数据（包括原子坐标）的球形位点和连接体。 我们将开发新的可选方案以更好地考虑分子结构的刚性 在这个粗粒度级别，以及链接器域的灵活性；后者会帮助我们 代表本质上无序域的影响。我们将开发统计和 分析方法来分析仿真结果并建立集总模型，以便从 这种介观尺度到全细胞尺度。最后，我们建议通过以下方式支持机械化学： 考虑到某个地点所经历的局部力并适当改变概率 解离率（解离率）、结合率（结合率）和膜表面的张力。最终， SpringSaLaD 功能将被纳入 Virtual Cell 软件系统中。

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.