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

化学部生命过程化学计划资助佐治亚州立大学的Samer Gozem博士研究光激发后光-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，必须感知并对不断变化的光照条件做出反应。LOV结构域是一类蛋白质，它使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相结合的方法来研究蛋白质中的特定氨基酸如何协调LOV结构域中黄素的电子结构在光吸收时的变化。这项研究将确立的基本原则对基于LOV的可编码生物传感器、光开关和活性氧生成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，使非计算学生和科学家更容易使用。高中生和本科生，包括那些来自代表不足的少数群体的学生，将被介绍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佐治亚州立大学的课程中引入一门将量子力学与化学和生物学联系起来的跨学科课程的影响。LOV光感受器与普遍存在的生物辅因子黄素结合，但与其他黄素蛋白光感受器进行不同的光化学。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，然后在热或某些情况下，通过光化学恢复到暗态。然而，这种机制的细节在不同的生物体中或在突变时有所不同。本项目将研究来自三个生命王国(植物、细菌和真菌)的典型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化如何改变黄素辅因子的光物理和光化学特性。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计算使用MM子系统进行，该子系统部分捕获了通过分子动力学模拟生成的蛋白质结构集合，以采样局部侧链灵活性。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势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.