Physics of Assembly and Disassembly of HIV

该奖项支持理论和计算研究，以及建立在对小型植物病毒和噬菌体病毒如何通过细菌感染和复制的成功理解的基础上的教育。这些成功是通过应用材料弹性理论和统计物理的方法取得的。该奖项支持为人类免疫缺陷病毒（艾滋病毒）的组织和结构发展建立物理模型的努力，这是一个更大的挑战。在其发育的早期“不成熟”阶段，HIV有一个厚厚的、看似坚固的蛋白质外壳，由包裹着基因组分子的非常大的蛋白质组成。这个外壳上有大洞，这对于一个坚固的容器来说是令人困惑的。壳通过多种化学反应分解。pi计划开发一个壳层形成和破裂的数值模型，该模型适当地结合了弹性材料的理论描述和统计物理学的概念，以解释孔洞的形成和壳层的协同破裂。该模型将与一个制造合成艾滋病毒外壳的试验组合作开发。在第二阶段，HIV基因组分子被包裹在一个非常脆弱和薄的蛋白质外壳中。第二个外壳的物理作用尚不清楚。pi的目标是为这种薄壳开发一种新的模型，在将病毒RNA转化为病毒DNA的关键HIV过程中，它扮演着化学反应容器的角色。当产生足够数量的刚性DNA材料，从而对容器壁施加足够的力时，反应堆容器破裂。pi将使用材料弹性理论来模拟这个成熟外壳的断裂。该项目的最后一部分涉及为宿主细胞内HIV外壳的早期发育建立一个数值模型，这也将与实验人员合作进行。这项研究涉及应用材料研究的方法和思想，以促进对大型病毒如何自组装的理解。除了可能导致管理病毒性疾病的新策略外，这项研究还更广泛地了解了由原子组成的大分子和其他结构从其组成的原子和分子构建块自组装的过程。这些基本原理可能会带来设计新材料的新方法，并从原子和分子的构建块中制造新材料。该奖项支持理论和计算研究，以及通过弹性理论和统计物理的应用方法成功地推进对小型植物和噬菌体病毒组装的理解的教育。更大的人类免疫缺陷病毒，HIV-1，根据非常不同的原理运作，对它们的了解有限。该奖项支持解决三个难题的努力：(1)像HIV这样的逆转录病毒经历了大规模的结构成熟转化，这是其生命周期的一部分，其中第二个“成熟”病毒颗粒在第一个“未成熟”病毒颗粒的内部组装。感染后，这个成熟的颗粒被插入宿主的细胞质中，以传递病毒基因组。这种转化是由巨大的Gag多蛋白协调的。未成熟形式的HIV病毒包括一个结构混乱的Gag蛋白外壳，其中包含大的，不规则形状的孔。为什么这些洞不闭合是一个谜。(2)病毒RNA分子对Gag的热力学亲和力与竞争的非病毒RNA分子大致相同，在初始组装时，非病毒RNA分子在宿主细胞中的含量要高得多；但不知何故，Gag相当有效地选择了病毒RNA分子进行封装。一般静电和特殊非静电相互作用之间的微妙相互作用以及Gag的结构转变能否解释这个谜题？(3) HIV的圆锥形成熟衣壳比几乎任何其他病毒的衣壳更脆弱，然而强化外壳或改变其形状的突变对HIV的传染性有强烈的负面影响。这三个难题将通过应用从软物质物理学、生物物理学和统计力学的不同领域借鉴的概念和方法来解决。这三个项目都将与侧重于艾滋病毒生物物理特性的实验室密切合作进行。从物理上理解Gag是如何在没有增强的热力学亲和性和没有任何校对的情况下从相似的分子池中选择分子的，这将是一个基本的兴趣。其次，被限制在球面上的粒子的多体物理被认为具有以疤痕状缺陷为特征的最小能态。Gag粒子在球形模板上的组装就表现出这样的伤痕。当模板被移除时，这些疤痕似乎演变成上面提到的不规则孔。将局限于可变形球面的粒子的基本物理学与未成熟的HIV衣壳联系起来，将为该领域的进一步发展提供刺激。最后，尽管弹性病毒衣壳的物理特性已被广泛研究，但非常脆弱的蛋白质壳的断裂物理特性尚不清楚。然而，控制衣壳断裂——就像HIV所做的那样——可能是设计新的药物输送系统的关键一步。

NONTECHNICAL SUMMARY This award supports theoretical and computational research, and education that builds on the successes in advancing understanding of how small plant viruses and bacteriophage viruses which infect and replicate through a bacterium assemble. These successes were made through the application of methods from the elastic theory of materials and statistical physics. This award supports efforts to develop a physical model for the organization and structural development of the human immunodeficiency virus (HIV), which presents a greater challenge. During an early "immature" stage of its development, HIV has a thick and seemingly robust protein shell composed of the very large proteins that enclose the genome molecule. This shell contains large holes, which is puzzling for a robust container. The shell breaks up through multiple chemical reactions. The PIs plan to develop a numerical model for the formation and break-up of the shell that properly incorporates a theoretical description of elastic materials and concepts from statistical physics to account both for hole formation and the cooperative break-up of the shell. The model will be developed in collaboration with an experimental group that makes synthetic HIV shells. During a second stage, HIV genome molecules are enclosed in a very fragile and thin protein shell. The physical role of this second shell is not understood. The PIs aim to develop a new model for this thin shell, where it plays the role of a chemical reaction vessel during the key HIV process that translates viral RNA into viral DNA. The reactor vessel breaks up when a sufficient amount of stiff DNA material has been produced so as to exert sufficient force on the container wall. The PIs will model the fracture of this mature shell using the theory of the elasticity of materials. The last part of the project involves developing a numerical model for the very early development of the HIV shell inside the host cell, which will also be carried out in collaboration with experimentalists. This research involves the application of methods and ideas from materials research to advance understanding of how large viruses self-assemble. Apart from potentially leading to new strategies for managing viral diseases, the research brings insight more generally to the process by which large molecules and other structures made from atoms self-assemble from their constituent atomic and molecular building blocks. The fundamental principles may lead to new ways to design new materials and manufacture them from atomic and molecular building blocks.TECHNICAL SUMMARY This award supports theoretical and computational research, and education that builds on the successes in advancing understanding of the assembly of small plant and bacteriophage viruses through the application methods from elasticity theory and statistical physics. The much larger human immunodeficiency virus, HIV-1, operates on very different principles and understanding of them is limited. This award supports efforts to resolve three puzzles: (1) Retroviruses like HIV undergo a massive structural maturation transformation as part of their life cycle in which a second "mature" viral particle is assembled in the interior of the first "immature" particle. After infection, this mature particle is inserted into the cytoplasm of the host to deliver the viral genome. This transformation is coordinated by the huge Gag polyprotein. The immature form of the HIV virus includes a structurally disorganized shell of Gag proteins that contains large, irregularly shaped holes. Why these holes do not close up is a puzzle. (2) The thermodynamic affinity of viral RNA molecules for Gag is about the same as that of competing non-viral RNA molecules, which are much more abundant in the host cell during the initial assembly; but somehow Gag quite efficiently selects the viral RNA molecules for encapsidation. Can a delicate interplay among generic electrostatic and specific non-electrostatic interactions as well as a structural transformation of Gag explain this puzzle?(3) The conical mature capsid of HIV is more fragile than the capsid of just about any other virus, yet mutations that strengthen the shell or that change its shape have a strongly negative impact on HIV infectivity. These three puzzles will be addressed through the application of concepts and methods borrowed from different areas of soft-matter physics, biological physics, and statistical mechanics. All three projects will be carried out in close collaboration with labs that focus on the biophysical properties of HIV. A physical understanding how it is possible for Gag to select molecules from a pool of similar molecules without either having an enhanced thermodynamic affinity and without any proofreading would be of fundamental interest. Next, the many-body physics of particles confined to a spherical surface is believed to have a minimum energy state characterized by scar-like defects. Assemblies of Gag particles on spherical templates exhibit just such scars. These scars appear to evolve into the irregular holes mentioned above when the template is removed. Connecting the fundamental physics of particles confined to deformable spherical surfaces with the immature HIV capsid would provide a stimulus for the further development of this field. Finally, though the physics of resilient viral capsids has been investigated extensively, the physics of fracture of very fragile protein shells is not understood. Yet controlled fracture of capsids - as practiced by HIV - may be a key step for the design of new drug delivery systems.