Collaborative Research: Geometric Elucidation of Supramolecular Assembly and Allostery with Experimental Validation

合作研究：超分子组装和变构的几何阐明与实验验证

• 批准号: 1563234
• 负责人: Meera Sitharam
• 金额: $ 80万
• 依托单位: University of Florida
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1563234&HistoricalAwards=false
• 关键词: Collaborative; Research; Geometric; Elucidation; Supramolecular

A wide variety of supramolecular structures in nature and engineering--from viruses to protein crystals to nanomaterials--assemble rapidly and spontaneously at room temperature with remarkable efficacy. Many assembly processes incorporate the phenomenon of allostery, where intermolecular interaction is controlled by binding events at a remote site of one of the interacting molecules. Despite increasingly sophisticated in vivo, in vitro and in silico experimental efforts, assembly processes are poorly understood. A more mathematically rigorous, and mechanistically intuitive theory is crucial not only to predict and engineer assembly and allostery but also to guide further time-consuming experimentation. Deeper understanding of assembly, allostery, and the role of the latter in the former will help control infectious diseases, assemble viral vectors for gene therapy, design drugs and engineer materials at the nanoscale.It is natural to expect that geometry and algorithmic complexity would play a key role in understanding the mechanisms underlying assembly, since the assembly process must crucially depend on the intricate shape and volume of the so-called assembly configuration space in which the molecules move relative to each other as they assemble. Conversely, it is also natural to expect that new mathematics, algorithms and software will result from the quest to understand intricate molecular configuration spaces and perform computations over them. The project's goals include new theorems and algorithms, their hybridization with prevailing methods, and opensource software. Progress is expected on long open problems in rigidity, configuration spaces, distance geometry; algorithms for efficient atlasing, search, sampling, and volume computation for high dimensional and topologically intricate configuration spaces; hybrid methods that combine the new algorithms with prevailing energy-based Monte Carlo simulation; and most significantly, concrete experimental validation of predictions. The project combines expertise in geometry and algorithms, experimental structural biology, and computational chemistry, and is well-suited for bringing the three communities together, for providing interdisciplinary training for research students as well as for outreach to schools and the public.

自然界和工程学中的各种超分子结构 - 从蛋白质晶体到纳米材料 - 在室温下迅速和自发地组装，具有明显的功效。 许多组装过程结合了变构现象，其中分子间相互作用是通过一个相互作用分子的远程位点的结合事件来控制的。 尽管体内，体外和计算机实验努力越来越复杂，但对组装过程的理解很少。 在数学上更严格，机械上直觉的理论不仅对于预测和工程组装和变构也至关重要，而且对于指导进一步的时间耗时的实验至关重要。 对组装，变构和后者在前者中的作用的更深入了解将有助于控制感染性疾病，组装基因治疗的病毒媒介，在纳米级上设计药物和工程师材料，很自然地期望几何学和算法复杂性在理解以下方面的组装方面的构造方面起着重要的作用，自来会在组合上既有构造的构造，又可以自发地构成组装的机制。分子在组装时相对移动的构型空间。 相反，也很自然地期望新的数学，算法和软件将是由于了解复杂的分子配置空间并对其进行计算而产生的。 该项目的目标包括新的定理和算法，与现行方法的杂交以及OpenSource软件。 在刚性，配置空间，距离几何形状方面的长时间开放问题上有望进展；用于高维和拓扑复杂的配置空间的有效地进行地理，搜索，采样和音量计算的算法；将新算法与主要基于能量的蒙特卡洛模拟相结合的混合方法；最重要的是，预测的具体实验验证。 该项目结合了几何学和算法，实验结构生物学和计算化学的专业知识，非常适合将这三个社区聚集在一起，用于为研究学生以及向学校和公众提供跨学科培训。