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

Wayne State University, Detroit MI

Investigators

Abstract

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.