RUI: Entanglements in Proteins and Other Macromolecular Chains

蛋白质是执行许多维持生命的细胞过程的分子链。为了使蛋白质发挥其功能，蛋白质必须“折叠”成所谓的“天然状态”。虽然折叠过程不能直接观察到，但现代实验技术使观察蛋白质在其天然状态下的3D结构成为可能。研究人员已经在许多蛋白质的天然状态中发现了结（就像鞋子上的结）、链（就像奥林匹克五环）和其他类型的缠结。此外，研究表明，这些蛋白质中的缠结抑制了进化，这表明缠结对蛋白质的功能至关重要，而不仅仅是宇宙偶然事件。目前还不清楚为什么缠结（增加折叠过程的复杂性）会对蛋白质有利，特别是因为错误折叠蛋白质的后果可能是毁灭性的。例如，错误折叠的蛋白质被认为与阿尔茨海默病、帕金森病和克雅氏病（类似于疯牛病的人类疾病）等疾病有关。此外，与艾滋病毒、百日咳、肥胖和其他疾病有关的蛋白质也被证明含有缠结。该项目的目标是开发计算工具并进行模拟，以更深入地了解蛋白质和其他分子链中的缠结类型。清楚地了解蛋白质缠结，以及缠结与蛋白质功能之间的关系，将有助于深入了解人类疾病，并可能成为设计下一代对抗疾病的药物的核心。PI是一个由多学科合作者和本科生研究人员组成的小组，他们将利用自己独特的技能实现两个主要目标。首先，之前已经提出了许多不同的技术来对开放曲线（如蛋白质）中的打结类型进行分类。在这个项目中，将比较这些不同的方法，并创建新的高效算法，以测量这些曲线中的打结类型。其次，分子链的物理性质会影响可以产生的缠结结构。例如，分子链通常被建模为具有一定的厚度，即在链周围有一个薄的不可穿透的管。该小组将研究结的类型及其结构如何随着不同的厚度值而变化。总之，这些项目旨在有效地分类蛋白质中的缠结，确定它们的位置，并确定一些物理性质如何影响所观察到的缠结。除了科学目标之外，这项资助还有广泛的教育目标。本科生将接受PI的培训并参与项目，在研究过程中获得内容知识和经验。学生将参加专业会议，并在讲座和海报中传播他们的发现。这些研究经验对于培养下一代STEM教育工作者、研究人员和实践者至关重要。为了获得广泛的受众，PI将继续积极地在国内和国际上向学生、非专业人士和多学科团体作报告。研究结果将发表在数学和科学期刊上。PI将组织跨学科会议，将传统上不同领域的科学家聚集在一起，并与世界各地的研究人员建立新的跨学科合作。此外，研究成果、数据和软件将通过万维网公开提供。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

Proteins are molecular chains which perform many of the cellular processes that sustain life. For a protein to perform its function, the protein must "fold" into what is called its "native state". While the folding process is not directly observable, modern experimental techniques make it possible to observe the 3D structure of proteins in their native states. Researchers have found knots (like knots in one's shoes), links (like the Olympic rings), and other types of entanglements in the native states of many proteins. Furthermore, it has been shown that the entanglements in these proteins have resisted evolution, suggesting that the entanglements are critical to the function of the proteins and not just a cosmic accident. It is unclear why entanglements (which add complexity to the folding process) would be advantageous to proteins, especially since the consequences of misfolding a protein can be devastating. For example, misfolded proteins are believed to be related to diseases such as Alzheimer's disease, Parkinson's disease, and Creutzfeldt-Jakob disease (the human analogue of Mad Cow Disease). In addition, proteins linked to HIV, whooping cough, obesity, and other ailments have been shown to contain entanglements. The goal of this project is to develop computational tools and run simulations to gain a deeper understanding of the types of entanglements seen in proteins and other molecular chains. A clear understanding of protein entanglement, and the relationship between entanglement and protein function, will provide insights into human ailments and could be central to the design of the next generation of drugs to battle the ailments.The PI, a multi-disciplinary group of collaborators, and undergraduate researchers will leverage their unique skill set towards two main objectives. First, a number of different techniques have been proposed previously to classify the type of knotting in open curves (such as proteins). In this project, these different methods will be compared, and new efficient algorithms created, to measure the types of knotting in these curves. Second, physical properties of molecular chains affect the structure of entanglements that can be created. For example, molecular chains are often modeled as having some thickness, i.e. there is a thin impenetrable tube about the chain. The group will study how the types of knots and their structures change with differing thickness values. Together, these projects aim to efficiently classify the entanglements in proteins, pinpoint their location, and determine how some physical properties affect the entanglements observed. In addition to the scientific goals, this grant has broad educational objectives. Undergraduate students will be trained by the PI and contribute to the projects, gaining both content knowledge and experience in the research process. The students will participate in professional meetings and disseminate their findings in talks and posters. These research experiences are essential in training the next generation of STEM educators, researchers, and practitioners. To reach a wide audience, the PI will continue to be active in giving presentations to students, non-specialists, and multidisciplinary groups, both domestically and internationally. The results will be published in mathematics and science journals. The PI will organize interdisciplinary conference sessions to bring together scientists from traditionally disparate fields and create new interdisciplinary collaborations with researchers across the world. Furthermore, the research results, data, and software generated as a part of this grant will be made publicly available via the world wide web.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.