Physics of Viral Structure and Assembly

该奖项支持凝聚态物理学和生物学接口的理论和计算研究。PI的目的是使用凝聚态物理学的基本方法研究大型病毒组装“中间体”的物理学。目前对病毒衣壳在衣壳蛋白或低聚物溶液中组装的描述遇到了比热能大两个数量级以上的自由能垒。这种屏障将禁止在热平衡条件下自发的病毒组装，这与已建立的体外组装研究相冲突。PI将通过应用从连续介质物理学中借用的方法来解决这个问题，特别是薄壳弹性理论，该理论已经被发现对研究病毒壳的形状和弹性响应很有用。分析研究将辅之以大规模数值研究，将病毒外壳物理学的有限元分析与蒙特-卡罗模拟相结合，以模拟大型病毒外壳的生长，并计算阻止组装的自由能垒。该提案的第二个目的是研究协同性对病毒组装的影响。早在1980年，弗兰克·卡斯帕（Frank Caspar）就提出，病毒组装类似于其他形式的蛋白质聚集，例如肌动蛋白丝的聚合，其中蛋白质的内部构象自由度已知在聚集过程中发挥关键的自我调节作用。PI已经确定了如何在病毒组装研究中定量实施这一概念，以及如何探索内部自由度对组装自由能垒的影响。作为正在进行的合作的一部分，他们将通过分析和数值计算，计算具有内部自由度的完整壳体的力-变形曲线，并通过CCMV的AFM研究来测试结果。该提案的智力价值在于应用了重要而强大的固体物理学方法，如Kosterlitz无源熔化，表面熔化，Wulff构造，软模不稳定性，和Grinfeld不稳定性对病毒的物理研究。拟议工作的更广泛的影响将是物理洞察的发展，允许大的，有序的纳米壳与有趣的潜在材料科学应用程序的控制自组装的条件。非技术摘要：该奖项支持凝聚态物理和生物学接口的理论和计算研究。PI计划应用基本凝聚态物理学的概念来理解蛋白质如何组装成纳米级病毒外壳的生物学问题。PI将探索这一过程与其他涉及蛋白质的自组装过程的关系。这项工作可能会对理解其他过程产生影响，在这些过程中，纳米级原子或分子的构建块自发地将自己排列成有趣的结构，其中一些在医学或更广泛的技术中具有潜在的应用。

TECHNICAL SUMMARY:This award supports theoretical and computational research at the interface of condensed matter physics and biology. The PI aims to study the physics of large viral assembly "intermediates" using fundamental methods of condensed matter physics. Current descriptions of the assembly of a viral capsid in a solution of capsid proteins, or oligomers, encounter a free energy barrier that is more than two orders of magnitude larger than the thermal energy. This barrier would forbid spontaneous viral assembly under conditions of thermal equilibrium, which conflicts with established in-vitro assembly studies. The PI will address this problem by applying methods borrowed from continuum physics, specifically the theory of elasticity of thin shells, which already has been found to be useful for the study of the shape and elastic response of viral shells. Analytical studies will be complemented by large-scale numerical studies combining finite-element analysis of the physics of viral shells with Monte-Carlo simulation in order to simulate the growth of a large viral shell and to compute the free-energy barrier against assembly. A second aim of the proposal is to study the effects of cooperativity on viral assembly. Frank Caspar proposed, already in 1980, that viral assembly is akin to other forms of protein aggregation, such as the polymerization of actin filaments, where the internal conformational degrees of freedom of the proteins are known to play a key self-regulatory role during aggregation. The PIs have determined how this concept can be quantitatively implemented in a study of viral assembly and how the effect of internal degrees of freedom on the assembly free energy barrier can be explored. They will compute, both analytically and numerically, the force-deformation curve of completed shells with internal degrees of freedom and test the results via AFM studies of CCMV, as part of an ongoing collaboration.The intellectual merit of the proposal lies in the application of important and powerful methods of solid-state physics, such as Kosterlitz-Thouless melting, surface melting, Wulff Construction, Soft-mode instability, and Grinfeld Instability to the physical studies of viruses. A broader impact of the proposed work would be the development of physical insight into the conditions that allow controlled self-assembly of large, ordered nanoshells with interesting potential materials science applications.NON-TECHNICAL SUMMARY:This award supports theoretical and computational research at the interface of condensed matter physics and biology. The PI plans to apply concepts of fundamental condensed matter physics to understand biologically inspired problem of how proteins assemble themselves into the nanoscale-sized shells of viruses. The PIs will explore the relationship of this process to other self-assembly processes involving proteins. The work may have impact on understanding other processes where nanoscale-sized building blocks of atoms or molecules spontaneously arrange themselves into interesting structures, some with potential applications in medicine or technology more generally.