Physics Virus of Assembly and Maturation: energetics and dynamics

组装和成熟的物理病毒：能量学和动力学

• 批准号: 1719550
• 负责人: Roya Zandi
• 金额: $ 33万
• 依托单位: University of California-Riverside
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-12-15 至 2021-11-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1719550&HistoricalAwards=false
• 关键词: Physics; Virus; Assembly; Maturation; energetics

Nontechnical SummaryThis award supports theoretical and computational research, and education at the interface of materials research and biology and is aimed to advance understanding of how RNA viruses assemble. They infect bacteria, plants, and animals among many other hosts, and with all degrees of severity. All viruses, from the simplest to the most complicated, are built from a protein shell called the capsid which protects the genetic materials (RNA or DNA) they contain. The focus of this project is on single stranded RNA viruses that under many circumstances readily assemble from solutions containing capsid proteins and genome molecules. Due to advances in experimental techniques that probe living and inanimate matter at the nanoscale, the number of experiments investigating the physical basis of self-assembly and maturation of viral particles are soaring. This research project involves applying the methods of elasticity theory, and statistical and polymer physics to develop a physical model to explain experiments related to the formation of different viruses. The PI will engage three related projects. The first is to understand the factors that contribute to the efficient assembly and stability of spherical viral particles. The PI will study how the shape of RNA or to be mathematically precise, RNA topology, affects the size, shape and stability of viral shells and how the capsid structure and charge density in turn influences the structure of the encapsulated RNA. The second project involves analyzing the structure of immature human immunodeficiency virus (HIV) shell built from protein subunits, packed with local hexagonal shape and surrounded by a lipid bilayer. An intriguing feature of the immature HIV-1 is the presence of small and large gaps, covering about 30% of the surface of the enclosing membrane. The origin of the gaps is not well understood. The PI will explore what physical properties of protein subunits give rise to the structures similar to the immature HIV shell. Finally, the last project is devoted to the process of maturation of the spherical immature HIV particles, which involves cleavage of HIV immature building blocks by a set of chemical reactions leading to the assembly of the intriguing HIV conical capsid. Through the understanding of the interplay of RNA shape and the way viral capsid structure emerges, this project will advance understanding of the process of self-assembly which shapes much of the biomolecular world as well as biomaterials and polymer-based materials.Understanding the physical factors that influence the formation of virus particles is currently finding applications in nanotechnology, actuators, drug delivery and gene therapy and can play a vital role in the development of new anti-viral therapies. Furthermore, this project will contribute to the education of undergraduate and graduate students, and particularly to the training of the next generation of soft condensed matter, polymer, and biological physicists in a multidisciplinary environment. The PI will also organize an outreach program for young women middle school students.Technical Summary This award supports theoretical and computational research and education at the interface of material science, soft condensed matter physics and biology. This project involves the extension of recent progress in the statistical theory of soft matter to the physics of viruses, which corresponds to the long-standing charge over-compensation problem in the physics of polyelectrolytes, the controversies about the impact of annealing and pseudoknots on the adsorption of RNA to the oppositely charged wall, and the structure of macromolecules under confinement. The research is focused on the statistical mechanics of viral self-assembly, both in equilibrium and far from equilibrium. The self-assembly and maturation of virus particles will be studied through developing new computational and theoretical models. The self-consistent field theory of polyelectrolytes needs to be extended to consider self-interaction of RNA while confined in a viral shell. Of particular interest is how the free energy of viral particles is influenced by the topology of RNA while interacting with the positively charged N-terminal domain of capsid proteins. The PI and her group will investigate the impact of the thermodynamic parameters on the size and geometry of the assembly products with the aim to explain the phenomena of co-existence and polymorphism observed in many virus assembly experiments. The PI combines the equilibrium statistical theory and classical nucleation theory to study how kinetic barriers influence the final structure of capsids. In view of complexity of the physics, in additional to analytical calculations, the PI will perform a series of both Monte Carlo and Brownian dynamics computer simulations to explore both the equilibrium and kinetic aspects of viral self-assembly and maturation. The important questions to be addressed are: What physical considerations govern the maturation of HIV particles? and What determines the ratio of different assembled structures from a solution of capsid proteins and genome molecules? The PI and her team will invetigate the impact of changes in the mechanical properties of coat proteins after protease cleavage, resulting in the transformation of the immature HIV to the mature conical capsid.

该奖项支持理论和计算研究，以及材料研究和生物学界面的教育，旨在促进对RNA病毒如何组装的理解。它们感染细菌、植物和动物以及许多其他宿主，并具有各种严重程度。所有的病毒，从最简单的到最复杂的，都是由一种叫做衣壳的蛋白质外壳组成的，衣壳保护着它们所包含的遗传物质（RNA或DNA）。这个项目的重点是单链RNA病毒，在许多情况下，很容易组装从含有衣壳蛋白和基因组分子的解决方案。 由于在纳米尺度上探测生命和无生命物质的实验技术的进步，研究病毒颗粒自组装和成熟的物理基础的实验数量正在飙升。该研究项目涉及应用弹性理论，统计和聚合物物理学的方法来开发物理模型，以解释与不同病毒形成相关的实验。PI将参与三个相关项目。首先是了解有助于球形病毒颗粒有效组装和稳定的因素。PI将研究RNA的形状或在数学上精确的RNA拓扑结构如何影响病毒外壳的大小，形状和稳定性，以及衣壳结构和电荷密度如何反过来影响封装RNA的结构。第二个项目涉及分析不成熟的人类免疫缺陷病毒（HIV）外壳的结构，该外壳由蛋白质亚基组成，具有局部六边形形状，并被脂质双层包围。未成熟的HIV-1的一个有趣的特征是存在大大小小的间隙，覆盖了封闭膜表面的约30%。差距的起源还不清楚。 PI将探索蛋白质亚基的哪些物理特性会产生与不成熟的艾滋病毒外壳相似的结构。最后，最后一个项目致力于球形未成熟HIV颗粒的成熟过程，该过程涉及通过一系列化学反应切割HIV未成熟构建模块，从而组装有趣的HIV锥形衣壳。通过对RNA形状和病毒衣壳结构出现方式的相互作用的理解，该项目将推进对自组装过程的理解，该过程塑造了大部分生物分子世界以及生物材料和聚合物基材料。了解影响病毒颗粒形成的物理因素目前正在纳米技术，致动器，药物输送和基因治疗，并可以在新的抗病毒疗法的发展中发挥至关重要的作用。此外，该项目将有助于本科生和研究生的教育，特别是在多学科环境中培养下一代软凝聚态物质，聚合物和生物物理学家。PI还将为年轻的女中学生组织一个外展计划。技术总结该奖项支持材料科学、软凝聚态物理学和生物学领域的理论和计算研究与教育。该项目涉及将软物质统计理论的最新进展扩展到病毒物理学，这对应于聚电解质物理学中长期存在的电荷过度补偿问题，关于退火和伪结对RNA吸附到相反电荷壁的影响的争议，以及限制下的大分子结构。该研究的重点是病毒自组装的统计力学，无论是在平衡和远离平衡。病毒粒子的自组装和成熟将通过开发新的计算和理论模型进行研究。自洽场理论的聚电解质需要扩展到考虑自相互作用的RNA，而被限制在一个病毒壳。特别令人感兴趣的是病毒颗粒的自由能如何受到RNA拓扑结构的影响，同时与衣壳蛋白的带正电荷的N-末端结构域相互作用。PI和她的团队将研究热力学参数对组装产物的大小和几何形状的影响，目的是解释在许多病毒组装实验中观察到的共存和多态现象。 PI结合了平衡统计理论和经典成核理论来研究动力学障碍如何影响衣壳的最终结构。 鉴于物理学的复杂性，除了分析计算外，PI还将进行一系列Monte Carlo和布朗动力学计算机模拟，以探索病毒自组装和成熟的平衡和动力学方面。需要解决的重要问题是：什么样的物理因素决定了HIV颗粒的成熟？是什么决定了衣壳蛋白和基因组分子溶液中不同组装结构的比例？PI和她的团队将研究蛋白酶切割后外壳蛋白机械性质变化的影响，导致未成熟的HIV转化为成熟的锥形衣壳。

项目成果

Effect of the charge distribution of virus coat proteins on the length of packaged RNAs

病毒外壳蛋白的电荷分布对包装RNA长度的影响

• DOI: 10.1103/physreve.102.062423
• 发表时间: 2020
• 期刊: Physical Review E
• 影响因子: 2.4
• 作者: Dong, Yinan;Li, Siyu;Zandi, Roya
• 通讯作者: Zandi, Roya

Investigation of HIV-1 Gag binding with RNAs and lipids using Atomic Force Microscopy

• DOI: 10.1371/journal.pone.0228036
• 发表时间: 2020-02-03
• 期刊: PLOS ONE
• 影响因子: 3.7
• 作者: Chen, Shaolong;Xu, Jun;Mohideen, Umar
• 通讯作者: Mohideen, Umar

Virus Mechanics under Molecular Crowding

分子拥挤下的病毒力学

• DOI: 10.1021/acs.jpcb.0c10947
• 发表时间: 2021
• 期刊: The Journal of Physical Chemistry B
• 作者: Zeng, Cheng;Scott, Liam;Malyutin, Andrey;Zandi, Roya;Van der Schoot, Paul;Dragnea, Bogdan
• 通讯作者: Dragnea, Bogdan

The equilibrium structure of self-assembled protein nano-cages

• DOI: 10.1039/c8nr07202g
• 发表时间: 2018-12-28
• 期刊: NANOSCALE
• 影响因子: 6.7
• 作者: Panahandeh, Sanaz;Li, Siyu;Zandi, Roya
• 通讯作者: Zandi, Roya

Ground States of Crystalline Caps: Generalized Jellium on Curved Space

晶体帽的基态：弯曲空间上的广义 Jellium

• DOI: 10.1103/physrevlett.123.145501
• 发表时间: 2019
• 期刊: Physical Review Letters
• 影响因子: 8.6
• 作者: Li, Siyu;Zandi, Roya;Travesset, Alex;Grason, Gregory M.
• 通讯作者: Grason, Gregory M.