Multiscale modeling of mechanisms for viral capsid assembly and polymorphism

病毒衣壳组装和多态性机制的多尺度建模

• 批准号: 7565125
• 负责人: MICHAEL F HAGAN
• 金额: $ 22.18万
• 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 2013-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7565125
• 关键词: Antiviral Agents; Base Pairing; Capsid; Capsid Proteins; Cells; Cereals; Charge; Collaborations; Computer Simulation; Data; Drug Delivery Systems; Drug resistance; Essential Amino Acids; Event; Genetic Polymorphism; Goals; Harvest; Image; Infection; Kinetics; Lead; Learning; Length; Light; Modeling; Molecular Conformation; Morphology; Mutate; Nature; Nucleic Acids; Organism; Pharmaceutical Preparations; Polymers; Process; Property; Protein Conformation; Protein Subunits; Proteins; RNA; Reaction; Research; Resistance; Resolution; Sampling; Site; Structure; Study models; System; Viral; Viral Proteins; Virus; Virus Diseases; Water; Work; base; conformational conversion; cowpea chlorotic mottle virus; density; driving force; experience; fighting; forging; multi-scale modeling; multiple drug use; nanoparticle; novel; polyanion; public health relevance; research study; simulation

DESCRIPTION (provided by applicant): During the replication of many viruses, hundreds to thousands of protein subunits assemble around the viral nucleic acid to form a protein shell called a capsid. Within their host organism, most viruses form one particular structure with astonishing fidelity; yet, recent experiments demonstrate that capsids can assemble with different sizes and morphologies to accommodate nucleic acids, inorganic nanoparticles, and polyanions with different sizes. This project will use computational models to determine the features of viral proteins and their cargoes that enable assembly to be so precise and yet so adaptable. We develop simplified representations of viral proteins and cargoes that range from rigid spheres to fluctuating polymers to model nucleic acids. With these models we will develop experimentally testable predictions for the mechanisms by which viral proteins dynamically encapsidate these objects, and which factors direct the assembly process towards a particular size and morphology. These coarse-grained models of the overall assembly process will be validated and guided by atomic-resolution simulations that examine the dynamic conformations of viral proteins. PUBLIC HEALTH RELEVANCE: Viral diseases and acquired drug resistance by viruses are major biomedical challenges. The most effective antiviral treatments fight acquired resistance by using use multiple drugs to target several steps in the infection process, but relatively few treatments target viral assembly. By identifying the features that make viral assembly successful, we can learn to block it and thereby create novel antivirus therapies.

描述（由申请人提供）：在许多病毒复制过程中，数百至数千种蛋白质亚基在病毒核酸周围组装，形成一个称为capsid的蛋白质壳。在其宿主有机体中，大多数病毒都形成了一种特殊的结构，具有惊人的忠诚。然而，最近的实验表明，衣壳可以用不同的尺寸和形态组装，以容纳核酸，无机纳米颗粒和不同尺寸的多支。该项目将使用计算模型来确定病毒蛋白及其货物的特征，使组装变得如此精确却如此适应性。我们开发了病毒蛋白和货物的简化表示，从刚性球到波动的聚合物到建模核酸。通过这些模型，我们将针对病毒蛋白动态封装这些对象的机制进行实验测试的预测，以及哪些因素将组装过程指向特定的大小和形态。这些整体组装过程的粗粒模型将得到原子分辨率模拟的验证和指导，这些模拟检查了病毒蛋白的动态构象。公共卫生相关性：病毒疾病和因病毒获得的耐药性是主要的生物医学挑战。最有效的抗病毒治疗方法通过使用多种药物针对感染过程中的几个步骤来对抗获得的抗药性，但相对较少的治疗方法是针对病毒组装的。通过识别使病毒组装成功的功能，我们可以学会阻止它，从而创建新颖的防病毒疗法。