CAREER: Dynamics of Computationally Designed Fluorescent Proteins

职业：计算设计的荧光蛋白的动力学

• 批准号: 2144396
• 负责人: Colin Smith
• 金额: $ 99.67万
• 依托单位: Wesleyan University
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-01 至 2026-11-30
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2144396&HistoricalAwards=false
• 关键词: CAREER; Dynamics; Computationally; Designed; Fluorescent

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.

该奖项的全部或部分资金根据《2021 年美国救援计划法案》（公法 117-2）提供。具有新活性、行为或目的的蛋白质的设计一直是一个重要的研究领域。计算蛋白质设计领域变得越来越复杂，不仅可以重新设计现有蛋白质，还可以完全从头开始创建蛋白质。该项目的目标是研究和优化经过计算设计的微观蛋白质的运动，这些蛋白质利用光来跟踪生物分子的位置并揭示生物体的内部运作。这将使这些和其他蛋白质机器的更先进版本成为可能，这些机器也可以帮助在化学水平上制造和回收材料。该项目将雇用几名研究生和本科生进行全日制研究，为他们的职业做好准备，计算和实验方法日益整合，以解决下一组重大科学挑战。这项工作将支持一系列新的基于课堂的研究项目，赋予本科生科学发现和推进知识的能力。来自科学、技术、工程和数学背景的学生将通过既定项目帮助他们过渡到大学并为研究生院做好准备。美国救援计划的资金用于支持这位处于职业生涯关键阶段的早期职业调查员。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。该项目重点关注蛋白质运动在光吸收和再发射（这一过程称为荧光）中的关键但经常被忽视的作用。我们将首先通过计算机模拟的详细分析和广泛的实验结构表征来确定哪些蛋白质形状增强或抑制荧光。其次，我们将通过重新设计和实验检查更亮的荧光蛋白变体来测试我们的模型。作为这些努力的一部分，我们将开发一种通用计算机算法，能够快速评估数千个潜在突变如何影响蛋白质的形状。第三，我们将研究其他重要特性的结构决定因素，例如蛋白质防止或促进荧光打开和关闭的能力。最终，该项目旨在详细了解如何重新设计这些荧光蛋白和其他蛋白，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价值和更广泛的影响审查标准。