CAREER: Shedding light on the Photochemistry of the LOV Class of Flavin Photoreceptors

化学部的生命过程化学项目正在资助来自格鲁吉亚州立大学的Samer Gozem博士，以研究光激发后光-氧-电压（LOV）蛋白质结构域中发生的分子和电子事件。地球表面的大部分能量来自太阳辐射。依赖太阳能的生物，如藻类和植物，必须感知和响应不断变化的光照条件。LOV结构域是一类蛋白质，它利用黄素分子吸收光线，帮助生物体感知环境。Gozem博士将应用经典和量子力学计算机模拟的组合来研究蛋白质中的特定氨基酸如何在光吸收时协调LOV结构域中黄素的电子结构变化。本研究建立的基本原则对基于LOV的可编码生物传感器、光开关和活性氧发生器的设计具有潜在的长期影响。该项目预计将开发自动化和用户友好的计算化学工具，更容易获得非计算的学生和科学家。高中生和本科生，包括来自代表性不足的少数群体的学生，将被引入到多学科科学和研究中，在研究沉浸活动中使用这些计算工具。另一个教育目标是评估在格鲁吉亚州立大学的课程中引入将量子力学与化学和生物学连接起来的跨学科课程的影响。LOV光感受器结合普遍存在的生物辅因子黄素，但经历与其他黄素蛋白光感受器不同的光化学。在激发时，LOV黄素经历系统间交叉到三重态，与附近保守的半胱氨酸残基形成加合物，诱导变构反应，然后热还原到暗态，或者在某些情况下，光化学还原到暗态。然而，这种机制的细节在不同的生物体中或在诱变后有所不同。该项目将研究来自三个生命王国（植物，细菌和真菌）的原型LOV结构域中LOV光循环的每个步骤的机制细节，并试图阐明LOV结构域蛋白质序列变异如何改变黄素辅因子的物理和光化学性质。在这项研究中开发和使用的计算方法包括静电调谐映射和混合量子力学/分子力学（QM/MM）工具。QM/MM计算是通过MM子系统进行的，该子系统部分捕获了分子动力学模拟产生的蛋白质结构系综，以采样局部侧链的灵活性。该奖项反映了NSF的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

The Chemistry of Life Processes Program in the Chemistry Division is funding Dr. Samer Gozem from Georgia State University to investigate the molecular and electronic events that occur in Light-Oxygen-Voltage (LOV) protein domains following light excitation. The earth’s surface receives the majority of its energy from solar radiation. Organisms that depend on solar energy, such as algae and plants, must sense and respond to changing light conditions. LOV domains are a class of proteins that use the molecule flavin to absorb light and help organisms sense their environments. Dr. Gozem will apply a combination of classical and quantum mechanical computer simulations to study how specific amino acids in the protein coordinate changes in the electronic structure of the flavin in LOV domains upon light absorption. The fundamental principles to be established by this study have potential long term impact for the design of LOV-based encodable biosensors, light switches, and generators of reactive oxygen species. The project is anticipated to develop automated and user-friendly computational chemistry tools that are more readily accessible to non-computational students and scientists. High school and undergraduate students, including those from under-represented minority groups, are to be introduced to multidisciplinary science and research using these computational tools in research immersion activities. An additional educational goal is to assess the impact of introducing an interdisciplinary course connecting quantum mechanics to chemistry and biology into the curriculum at Georgia State University.LOV photoreceptors bind the ubiquitous biological cofactor flavin, but undergo distinct photochemistry from other flavoprotein photoreceptors. Upon excitation, the LOV flavin undergoes intersystem crossing to a triplet state, forms an adduct with a nearby conserved cysteine residue, induces an allosteric response, and then reverts to the dark state thermally or, in some cases, photochemically. However, the details of this mechanism vary in different organisms or upon mutagenesis. This project will investigate the mechanistic details of each step of the LOV photocycle in prototypical LOV domains from three kingdoms of life (plants, bacteria, and fungi) and seeks to elucidate how LOV domain protein sequence variations alter the photophysical and photochemical properties of the flavin cofactor. The computational methods being developed and employed in this research include electrostatic tuning maps and hybrid quantum mechanical/molecular mechanical (QM/MM) tools. The QM/MM calculations are being performed with an MM subsystem that partially captures the protein structural ensemble generated by molecular dynamics simulations to sample local side chain flexibility.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.