Multi-resolution Approaches to Modeling the 3D Structure, Delivery, and Replication of Viral Genomes

该项目将为病毒感染的定量研究开发计算方法。在这些问题的核心 Approach是对核酸和蛋白质的多分辨率描述，允许混合分辨率 非常大的生物分子系统的模拟，精确的分辨率从粗到细的切换，反之亦然， 包括完全原子化的表示，以及用于解释生化转换的显式机制。 在最近的DNA多分辨率模型的基础上，该项目将开发一种计算方法 确定病毒基因组在加压和自组装的病毒衣壳内的物理组织。这个 该方法将应用于以适合于药物的分辨率来解析几个包装的基因组的结构 开发应用程序。同时，细菌和真核细胞质的多分辨率模型将被 用来解释胞质蛋白与双链的特异性和非特异性相互作用 DNA该模型将被应用于确定喷射到体内的双链基因组的空间组织 并评价细胞质样环境对排出过程的影响。多种多样- 分辨率模拟框架将阐明控制基因组弹射的微观因素和 通过核孔复合体运输完整的病毒颗粒。最后，该项目将开发出第一个 病毒基因组复制的物理模型，考虑了必要的生化转换及其影响 外力对反应率的影响。复制模型将用于确定 宿主细胞的DNA结合蛋白影响病毒基因组复制的保真度。多分辨率仿真 通过该程序开发的方法将在GPU加速代码原子解析中实现 布朗动力学。方法和代码，以及所有必需的文档、示例和教程， 将免费向研究界提供，以研究广泛的生物物理过程。

This project will develop computational approaches for quantitative studies of viral infection. At the core of these approaches is a multi-resolution description of nucleic acids and proteins that permits mixed-resolution simulations of very large biomolecular systems, accurate resolution switching from coarse to fine and vice versa, including a fully atomistic representation, and an explicit mechanism to account for biochemical transformations. Building on a recent multi-resolution model of DNA, the project will develop a computational method for determining the physical organization of viral genomes inside pressurized and self-assembled viral capsids. The method will be applied to resolve the structure of several packaged genomes at a resolution suitable for drug development applications. In parallel, a multi-resolution model of bacterial and eukaryotic cytoplasm will be developed to account for specific and nonspecific interactions of the cytoplasmic proteins with double-stranded DNA. The model will be applied to determine the spatial organization of double-stranded genomes ejected into cytoplasm and to evaluate the effect of the cytoplasm-like environment on the ejection process. The multi- resolution simulation framework will elucidate the microscopic factors governing genome ejection and the transport of an intact viral particle through a nuclear pore complex. Finally, the project will develop the first physical model of a viral genome replication, accounting for essential biochemical transformations and the effect of external forces on the reaction rates. The replication model will be used to determine how competition between DNA binding proteins of the host cell affect viral genome replication fidelity. The multi-resolution simulation methods developed through this program will be implemented in a GPU-accelerated code Atomic Resolution Brownian Dynamics. The methods and the code, along with all required documentation, examples and tutorials, will be made freely available to the research community to study a wide range of biophysical processes.