CAREER: Dynamics of Computationally Designed Fluorescent Proteins

该奖项的全部或部分资金来自《2021年美国救援计划法案》(公法117-2)。设计具有新的活性、行为或目的的蛋白质一直是一个重要的研究领域。计算机蛋白质设计领域正变得越来越复杂，不仅可以重新设计现有的蛋白质，还可以完全从头开始创造蛋白质。该项目的目标是研究和优化微观的、通过计算设计的蛋白质的运动，这些蛋白质利用光来跟踪生物分子的位置，并揭示生物有机体的内部工作。这将使这些和其他蛋白质机器的更先进版本的创造成为可能，这些机器也可以帮助在化学层面上制造和回收材料。该项目将雇用几名研究生和本科生进行全日制研究，为他们的职业生涯做好准备，在这些职业中，计算方法和实验方法越来越多地结合在一起，以解决下一组重大科学挑战。这项工作将支持一套新的以班级为基础的研究项目，赋予本科生科学发现和推进知识的能力。来自科学、技术、工程和数学专业背景不足的学生将通过帮助他们过渡到大学和准备研究生院的既定计划来获得帮助。美国救援计划的资金被用来支持这位早期职业调查员在他职业生涯的关键阶段。虽然蛋白质的结构几乎总是功能所必需的，但它往往是不够的。这个项目的重点是蛋白质运动在实现光的吸收和再发射方面的关键但经常被忽视的作用，这一过程被称为荧光。我们将首先通过详细的计算机模拟分析和广泛的实验结构表征来确定哪些蛋白质形状可以增强或抑制荧光。其次，我们将通过重新设计和对更亮的荧光蛋白变体进行实验检查来测试我们的模型。作为这些努力的一部分，我们将开发一种通用的计算机算法，能够快速评估数千种潜在的突变如何影响蛋白质的形状。第三，我们将研究其他重要性质的结构决定因素，如蛋白质阻止或促进荧光开关的能力。最终，该项目旨在详细了解如何重新设计这些荧光蛋白质和其他蛋白质，使其成为生物研究和工业过程中真正有用的工具。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

This award is funded in whole or in part under the American Rescue Plan Act of 2021 (Public Law 117-2). The design of proteins with novel activity, behavior, or purpose has been an important area of research. The field of computational protein design is becoming increasingly sophisticated, enabling not only the redesign of existing proteins but also the creation of proteins entirely from scratch. The goal of this project is to study and optimize the movement of microscopic, computationally designed proteins that use light to track the locations of biological molecules and reveal the inner working of living organisms. This will enable the creation of even more advanced versions of these and other protein machines that can also help in the manufacture and recycling of materials at the chemical level. The project will employ several graduate and undergraduate students in full-time research, preparing them for careers where computational and experimental methods are increasingly integrated to solve the next set of major scientific challenges. This work will support a suite of new class-based research projects, empowering undergraduates in scientific discovery and advancing knowledge. Students from backgrounds underrepresented in science, technology, engineering, and mathematics will be reached through established programs assisting the transition to college and preparation for graduate school. American Rescue Plan funding is used to support this early career investigator at a critical stage in his career.While the structure of a protein is almost always necessary for function, it is often not sufficient. This project focuses on the critical but often neglected role of protein motion in enabling absorbance and reemission of light, a process known as fluorescence. We will first determine which protein shapes either enhance or inhibit fluorescence through detailed analysis of computer simulations and extensive experimental structural characterization. Second, we will test our models through redesign and experimental examination of brighter fluorescent protein variants. As part of these efforts, we will develop a general-purpose computer algorithm that enables rapid evaluation of how thousands of potential mutations affect the shape of the protein. Third, we will investigate the structural determinants of other important properties like the ability of the protein to prevent or facilitate switching fluorescence on and off. Ultimately, this project aims to develop a detailed understanding of how these fluorescent proteins and others can be redesigned to make them truly useful tools for biological research and industrial processes.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.