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：
10626860
负责人：
Aleksei Aksimentiev
金额：
$ 29.28万
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 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10626860
关键词：
3-Dimensional Acceleration Accounting Adopted Affect Affinity Algorithms Bacterial Model Bacteriophages Binding Binding Proteins Biochemical Biochemistry Biological Models Biological Process Biophysical Process Calibration 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 Membrane 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 Viral Packaging Virus Virus Assembly Virus Diseases Virus Replication ZIKA computer framework drug development ds-DNA enzyme model experimental study improved in vivo innovation molecular dynamics particle physical model pressure programs protein folding reaction rate self assembly 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的定量研究的计算方法。这些核心方法是对核酸和蛋白质的多分辨率描述，该描述允许混合分辨率非常大的生物分子系统的模拟，准确的分辨率从粗糙到细小，反之亦然，反之亦然，包括完全原子的表示，以及考虑生化转化的明确机制。该项目以最新的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的病毒式衣壳内病毒基因组的物理组织。这方法将用于解决适合药物的分辨率的几个包装基因组的结构开发应用。同时，细菌和真核细胞质的多分辨率模型将是开发是为了说明细胞质蛋白与双链的特定和非特异性相互作用脱氧核糖核酸。该模型将用于确定被弹出到的双链基因组的空间组织细胞质并评估细胞质样环境对弹出过程的影响。多分辨率仿真框架将阐明控制基因组弹出的微观因素和完整的病毒颗粒通过核孔复合物的运输。最后，该项目将开发第一个病毒基因组复制的物理模型，考虑到必需的生化转化和效果反应速率的外力。复制模型将用于确定如何宿主细胞的DNA结合蛋白会影响病毒基因组复制保真度。多分辨率模拟通过此程序开发的方法将以GPU加速代码原子分辨率实现布朗动态。方法和代码以及所有必需的文档，示例和教程，将自由地向研究界免费使用，以研究广泛的生物物理过程。