CAREER: Computational Design of Fluorescent Proteins with Multiscale Excited State QM/MM Methods

职业：利用多尺度激发态 QM/MM 方法进行荧光蛋白的计算设计

• 批准号: 2338804
• 负责人: Alice Walker
• 金额: $ 69.08万
• 依托单位: Wayne State University
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2024
• 资助国家: 美国
• 起止时间: 2024-04-01 至 2029-03-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2338804&HistoricalAwards=false
• 关键词: CAREER; Computational; Design; Fluorescent; Proteins

With the support of the Chemistry of Life Processes (CLP) program in the Division of Chemistry, Alice Walker from Wayne State University is investigating the design of fluorescent protein sensors with computer simulations, including quantum and classical physics. Fluorescent proteins are widely used to watch and track biochemistry in living cells. However, the relationship between specific motions and structures of the protein and how this relates to the light-catalyzed motion of the chromophore is not fully understood. The proposed computational work will provide insight into these relationships with techniques that model the motion of the entire fluorescent protein and its reaction to light. This line of research is expected to support the development of new monomeric, red anion sensors, tunable photoswitchable dimers, and potentially create broadly applicable rational design principles to create new sensors. This project includes virtual and classroom-based research experiences in computational chemistry for undergraduate students. The goal of this research project is to apply computational chemistry to the understanding and rational design of new fluorescent protein (FP) sensors. FPs are used ubiquitously in biochemical experiments and as tools in chemical biology, where they can be applied to image molecules or mechanisms of interest. The development of new FP sensors is largely empirical—the relationship between the atomic details of the protein structure and photophysics of FP chromophores is not well understood. This fundamental knowledge gap makes the creation of targeted FP sensors especially challenging. Our central hypothesis that there is a physical relationship between the structural ensemble of the protein on the ground state and the motion of the chromophore on the excited state that, if clearly understood, could aid in the creation of new sensors. To test this hypothesis, the Walker team will use a combined approach of classical molecular dynamics (MD), excited state nonadiabatic quantum mechanical/molecular mechanical (QM/MM) dynamics, and machine learning (ML) to investigate specific systems with the aims of developing new fluorescent probes and establishing rational design principles for FP sensors more generally. This work will characterize the impact of surface mutations on the homotetrameric Dicosoma red fluorescent protein vs monomeric derivatives, design and study new anion-specific red FP sensors based on NeonGreen and endeavor to determine the mechanism of action for photodissociative Dronpa dimers.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.

在化学系生命过程化学（CLP）项目的支持下，韦恩州立大学的Alice Walker正在研究利用计算机模拟设计荧光蛋白传感器，其中荧光蛋白被广泛用于观察。然而，蛋白质的特定运动和结构之间的关系以及其与发色团的光催化运动的关系尚未完全了解。所提出的计算工作将通过技术提供对这些关系的深入了解。模拟整个荧光蛋白的运动及其对光的反应，预计这一系列研究将支持新型单体、红阴离子传感器、可调谐光开关二聚体的开发，并有可能创建广泛适用的合理设计原则来创建新的传感器。该项目包括为本科生提供计算化学方面的虚拟和基于课堂的研究经验，该研究项目的目标是将计算化学应用于生化实验中普遍使用的新型荧光蛋白（FP）传感器的理解和合理设计。并作为工具化学生物学，它们可以应用于图像分子或感兴趣的机制，新的 FP 传感器的开发很大程度上是经验性的——蛋白质结构的原子细节和 FP 发色团的光物理学之间的关系尚不清楚。我们的核心假设是，基态蛋白质的结构整体与激发态发色团的运动之间存在物理关系，如果清楚地理解这一关系，可能有助于实现目标 FP 传感器的创建。创造新的为了测试这一假设，Walker 团队将使用经典分子动力学 (MD)、激发态非绝热量子力学/分子力学 (QM/MM) 动力学和机器学习 (ML) 的组合方法来研究具有传感器的特定系统。目的是开发新的荧光探针并更广泛地建立 FP 传感器的合理设计原则。这项工作将表征表面突变对同源二聚体红色荧光蛋白与单体衍生物的影响，设计和研究基于新型阴离子特异性红色 FP 传感器。 NeonGreen 并致力于确定光解 Dronpa 二聚体的作用机制。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进行评估，被认为值得支持。