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

病毒基因组 3D 结构、传递和复制建模的多分辨率方法

基本信息

批准号：
10201674
负责人：
Aleksei Aksimentiev
金额：
$ 28.67万
依托单位：
UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10201674
关键词：
3-Dimensional Accounting Adopted Affect Affinity Algorithms Bacterial Model Bacteriophages Binding Binding Proteins Biochemical Biochemistry Biological Models Biological Process Biophysical Process Capsid Cell Nucleus Cells Code Communities Computer Models Computing Methodologies Cytoplasm Cytoplasmic Protein DNA DNA Structure DNA biosynthesis DNA metabolism DNA-Binding Proteins Data Development Disease Documentation Drug Targeting Environment Enzymes Genetic Materials Genome Grain Health Hepatitis B Herpesviridae Human In Vitro Individual Infection Knowledge Length Life Measurement Methods Microscopic Modeling Molecular Nuclear Pore Nuclear Pore Complex Nucleic Acids Organelles Outcome Pharmacological Treatment Physics Physiological Planet Earth Population Process Proliferating Proteins RNA Viruses Replication-Associated Process Research Resolution Solvents Structure System Time Viral Viral Genome Virus Virus Diseases Virus Replication ZIKA base computer framework drug development ds-DNA experimental study improved in vivo innovation molecular dynamics particle physical model pressure programs protein folding reaction rate simulation single molecule submicron three dimensional structure three-dimensional modeling viral DNA virology

项目摘要

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.

该项目将开发用于病毒感染定量研究的计算方法。这些的核心方法是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，从粗略到精细的精确分辨率切换，反之亦然，包括完全原子的表示，以及解释生化转化的明确机制。该项目以最近的 DNA 多分辨率模型为基础，将开发一种计算方法确定加压和自组装病毒衣壳内病毒基因组的物理组织。这该方法将用于以适合药物的分辨率解析几个包装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是开发用于解释细胞质蛋白与双链的特异性和非特异性相互作用脱氧核糖核酸。该模型将用于确定喷射到的双链基因组的空间组织。细胞质并评估类细胞质环境对喷射过程的影响。多分辨率模拟框架将阐明控制基因组喷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，该项目将开发第一个病毒基因组复制的物理模型，解释了基本的生化转化及其影响外力对反应速率的影响。复制模型将用于确定之间的竞争方式宿主细胞的 DNA 结合蛋白影响病毒基因组复制保真度。多分辨率模拟通过该计划开发的方法将在 GPU 加速的代码中实现原子分辨率布朗动力学。方法和代码，以及所有必需的文档、示例和教程，将免费提供给研究界以研究广泛的生物物理过程。