RUI: Entanglements in Proteins and Other Macromolecular Chains

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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.