Computational modeling of viral assembly: encapsulation of nucleic acids and env

病毒组装的计算模型：核酸和环境的封装

• 批准号: 8729612
• 负责人: MICHAEL F HAGAN
• 金额: $ 25.91万
• 依托单位: BRANDEIS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-12-01 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8729612
• 关键词: Affect; Alphavirus; Animal Viruses; Antiviral Agents; Antiviral Therapy; Base Pairing; Biological; Biology; Capsid; Capsid Proteins; Cell membrane; Cells; Cereals; Charge; Cholesterol; Complex; Computer Simulation; Drug Delivery Systems; Drug resistance; Electrostatics; Equilibrium; Family; Genetic Polymorphism; Genomics; Geometry; Goals; HIV; Hepadnaviridae; Hepatitis B Virus; Infection; Influenza; Investigation; Kinetics; Lead; Learning; Length; Lipids; Macromolecular Complexes; Mediating; Membrane; Membrane Microdomains; Membrane Proteins; Methodology; Methods; Modeling; Morphology; Nucleic Acids; Nucleocapsid; Polymers; Process; Property; Protein Conformation; Proteins; RNA; Reaction; Research; Resistance; Retroviridae; Shapes; Simian virus 40; Simulate; Sphingolipids; Structure; Techniques; Testing; Thermodynamics; Time; Variant; Viral; Viral Matrix Proteins; Virion; Virus; Virus Assembly; Virus Diseases; Work; cluster computing; conformational conversion; cowpea chlorotic mottle virus; design; fighting; membrane assembly; multiple drug use; nanoparticle; novel; nucleic acid structure; particle; physical property; prevent; public health relevance; research study; scaffold; simulation; viral RNA

DESCRIPTION (provided by applicant): In many virus families, replication requires that hundreds to thousands of proteins assemble around the viral nucleic acid (NA) to form a protein shell called a capsid. Furthermore, many animal viruses use protein assembly to drive budding of the capsid from a cell membrane. Understanding the mechanisms that control assembly around NAs and on membranes would identify targets for novel antivirus therapies that inhibit NA packaging or budding, and would guide efforts to exploit viruses as targeted transport vehicles. Assembly mechanisms inferred from experiments alone are incomplete because intermediates are transient. Therefore, this project develops and applies computational models for capsid proteins, NAs, and lipids that reveal details of assembly and membrane budding not accessible to experiments. To understand how the properties of viral NAs facilitate assembly, models are developed for capsid proteins and NAs that begin with a linear polyelectrolyte (without base-pairing) and then systematically add the geometric and electrostatic features of NAs that arise due to base-pairing. Comparison of predicted assembly kinetics and thermodynamics for each model identifies the contributions of base-pairing to assembly. Predictions for each model are tested against experiments performed by collaborating labs on capsid assembly around corresponding molecules (e.g., synthetic polyelectrolytes, heterologous NAs, and viral genomic NAs). The mechanism by which capsids form different icosahedral morphologies to accommodate NAs with different sizes is also studied. Employed simulation techniques include Brownian dynamics and equilibrium calculations. For some enveloped viruses (e.g., HIV) capsid assembly drives budding from a cell membrane, while for others (e.g., alphaviruses) assembly of membrane proteins drives budding of a pre-assembled capsid. Simulations are used to investigate how these two classes of assembly-driven budding processes depend on properties such as protein interactions and membrane rigidity, and why many viruses preferentially bud from particular membrane microdomains. Predictions will be compared to experiments on alphavirus budding. In addition to identifying factors that can be manipulated to prevent or exploit viral assembly, the proposed simulations will elucidate how biology employs membranes and filamentous scaffolds to assemble multi- macromolecular complexes. The research combines coarse-grained models that are informed by atomistic simulations and experiments with recent advances in GPUs and distributed computing to simulate relevant time and length scales. A new method to apply Markov state models to assembly reactions is developed.

描述（由申请人提供）：在许多病毒家族中，复制要求在病毒核酸（NA）周围组装数百至数千种蛋白质，以形成一种称为capsid的蛋白质壳。此外，许多动物病毒使用蛋白质组装来从细胞膜中驱动衣壳的发芽。了解在NAS和膜上控制组装的机制将确定抑制NA包装或萌芽的新型防病毒疗法的靶标，并指导将病毒作为目标运输车辆的努力。仅从实验推断出的组装机制是不完整的，因为中间体是短暂的。因此，该项目开发和应用计算模型，以揭示实验无法访问的组装和膜萌芽的细节，以揭示带蛋白，NAS和脂质。为了了解病毒NAS的特性如何促进组装，为带有线性聚电解质（无基碱取代）开头的衣壳蛋白和NAS开发了模型，然后系统地添加NAS的几何和静电特征，由于碱基对而产生。每种模型的预测组装动力学和热力学的比较都确定了碱基对组装的贡献。通过在相应分子（例如合成聚电解质，异源NAS和病毒基因组NAS）上协作实验室进行的实验进行测试，以测试每个模型的预测。还研究了衣壳形成不同二十面体形态以适应具有不同尺寸的NA的机制。采用的模拟技术包括布朗动力学和平衡计算。对于某些包膜病毒（例如HIV）的衣壳组件从细胞膜中启动，而对于其他膜（例如，α病毒）组装的膜蛋白组装驱动了预组装的帽子的萌芽。模拟用于研究这两类组装驱动的发芽过程如何取决于诸如蛋白质相互作用和膜刚度等特性，以及为什么许多病毒从特定的膜微区域中优先芽。预测将与α病毒芽的实验进行比较。除了确定可以操纵的因素以预防或开发病毒装配外，提出的模拟还将阐明生物学如何利用膜和丝状支架来组装多大分子分子复合物。该研究结合了由原子模拟和实验告知的粗粒模型，以及GPU和分布式计算的最新进展，以模拟相关的时间和长度尺度。开发了一种将马尔可夫状态模型应用于组装反应的新方法。