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.

在化学过程中的化学过程（CLP）方案的支持下，韦恩州立大学的爱丽丝·沃克（Alice Walker）正在研究使用计算机模拟（包括量子和经典物理学）的荧光蛋白传感器的设计。荧光蛋白被广泛用于观察和跟踪活细胞中的生物化学。然而，尚不完全了解蛋白质的特定运动与蛋白质结构之间的关系以及与发色团的光催化运动的关系。所提出的计算工作将通过对整个荧光蛋白的运动及其对光的反应进行模拟的技术来洞悉这些关系。预计这一研究将支持新的单体，红色阴离子传感器，可调的照片开关二聚体的开发，并可能创建广泛适用的理性设计原理来创建新的传感器。该项目包括针对本科生的计算化学研究经验。该研究项目的目的是将计算化学应用于新荧光蛋白（FP）传感器的理解和合理设计。 FPS在生化实验中普遍存在，并用作化学生物学的工具，可以将它们应用于图像分子或感兴趣的机制。新的FP传感器的开发在很大程度上是经验的 - 尚不清楚蛋白质结构的原子细节与摄影的原子细节之间的关系尚不清楚。这种基本知识差距使创建有针对性的FP传感器特别挑战。我们的核心假设是，蛋白质在基态的结构合奏与发色团的运动之间存在物理关系，即如果清楚地理解，可以帮助创建新传感器。为了检验这一假设，Walker团队将使用经典分子动力学（MD），激发状态非绝热量子机械/分子机械（QM/MM）动力学以及机器学习（ML）的组合方法来研究特定系统，目的是开发新的荧光问题并建立FP传感器的合理设计原理。这项工作将表征表面突变对同型双膜瘤红色荧光蛋白与单体衍生物的影响，设计和研究基于neongreen的新型阴离子特异性红色FP传感器，并确定努力的努力，以确定通过Infortial deem deem deem deem deem deempa deempa dronpa dem的作用机制。更广泛的影响审查标准。