Latham Andrew P, Tempkin Jeremy O B, Otsuka Shotaro, Zhang Wanlu, Ellenberg Jan, Sali Andrej
Department of Bioengineering and Therapeutic Sciences, Department of Pharmaceutical Chemistry, Quantitative Biosciences Institute, University of California, San Francisco, San Francisco, CA 94143, USA.
Cell Biology and Biophysics Unit, European Molecular Biology Laboratory, Heidelberg, Germany.
bioRxiv. 2024 Aug 8:2024.08.06.606842. doi: 10.1101/2024.08.06.606842.
Dynamic processes involving biomolecules are essential for the function of the cell. Here, we introduce an integrative method for computing models of these processes based on multiple heterogeneous sources of information, including time-resolved experimental data and physical models of dynamic processes. We first compute integrative structure models at fixed time points and then optimally select and connect these snapshots into a series of trajectories that optimize the likelihood of both the snapshots and transitions between them. The method is demonstrated by application to the assembly process of the human Nuclear Pore Complex in the context of the reforming nuclear envelope during mitotic cell division, based on live-cell correlated electron tomography, bulk fluorescence correlation spectroscopy-calibrated quantitative live imaging, and a structural model of the fully-assembled Nuclear Pore Complex. Modeling of the assembly process improves the model precision over static integrative structure modeling alone. The method is applicable to a wide range of time-dependent systems in cell biology, and is available to the broader scientific community through an implementation in the open source software.
涉及生物分子的动态过程对于细胞功能至关重要。在此，我们介绍一种基于多种异构信息源（包括时间分辨实验数据和动态过程的物理模型）来计算这些过程模型的综合方法。我们首先在固定时间点计算综合结构模型，然后最优地选择并将这些快照连接成一系列轨迹，以优化快照及其之间转换的似然性。该方法通过应用于有丝分裂细胞分裂过程中正在重塑的核膜背景下人类核孔复合体的组装过程得以证明，其依据是活细胞相关电子断层扫描、经体荧光相关光谱校准的定量活细胞成像以及完全组装好的核孔复合体的结构模型。与仅进行静态综合结构建模相比，组装过程的建模提高了模型精度。该方法适用于细胞生物学中广泛的时间相关系统，并且通过开源软件中的实现可供更广泛的科学界使用。
