Impact of Collective Motions on Protein Function

集体运动对蛋白质功能的影响蛋白质是负责几乎所有生命过程的分子机器。蛋白质通常必须改变它们的形状才能发挥作用。某些蛋白质如何能如此有效地改变形状，以及为什么其他蛋白质不能，目前尚不清楚。一个可能的答案在于这些分子的振动。该项目为改进预测蛋白质形状变化的计算提供了必要的数据。这项工作使用了一种独特的实验设置来测量蛋白质的振动，以及一种合作的方法来提高基于实验测量的计算的预测能力。这项研究将培养研究生和本科生进行跨学科研究(光学物理、分子生物学、材料科学和计算化学)。此外，大量本科生和高中生将参与体验式学习，动手测量和计算对光响应的蛋白质，如参与光合作用的捕光蛋白质。为了提高国际和文化意识，学生们将在墨西哥的一名合作者的支持下，参与研究并制作西班牙语教学媒体。研究人员将通过应用一种直接测量蛋白质分子内振动运动的独特工具：各向异性太赫兹显微镜(ATM)来研究分子内运动在蛋白质功能中的作用。这项工作将集中在几种基准蛋白质上，这些蛋白质已经被其他技术广泛研究，以表征结构和动力学。结合分子模拟，光活性黄蛋白(PYP)、蛋清溶菌酶(CEWL)和二氢叶酸还原酶(DHFR)及其突变体的ATM测量将识别影响功能的长程结构运动。PYP上的测量将检查蛋白质骨架内的振动是否会增强光活性蛋白质的发色团异构化，如眼睛中的光感应蛋白质、视紫红质。建议的测量将确定集体振动是否与PYP生色团的振荡重叠，以及光循环是否受到频率失谐的影响。这些测量还将检查CEWL和DHFR的远程突变是否通过扰乱分子内动力学来影响催化速率。PI和co-PI将改进计算蛋白质溶液和晶体的各向同性和各向异性太赫兹吸光度的方法，并开发与观测到的共振相对应的运动分析方法。

Title: Impact of Collective Motions on Protein FunctionProteins are molecular machines responsible for nearly all of life's processes. Proteins often must change their shape in order to do their work. How certain proteins can change shape so efficiently, and why others cannot, is not known. A possible answer lies in vibrations of these molecules. This project provides necessary data to improve calculations to predict protein shape changes. The work uses a unique experimental setup to measure protein vibrations, as well as a collaborative approach to improve the predictive power of calculations based on the experimental measurements. The research will train graduate students and undergraduates in interdisciplinary research (optical physics, molecular biology, materials science and computational chemistry). In addition, a large number of undergraduates and high school students will participate in experiential learning, with hands-on measurements and calculations on proteins that respond to light such as light harvesting proteins involved in photosynthesis. To increase international and cultural awareness, students, supported by a collaborator in Mexico, will participate in the research and produce instructional media in Spanish. The researchers will investigate the role of intramolecular motions in protein function by applying a unique tool developed to directly measure protein intramolecular vibrational motions: anisotropy terahertz microscopy (ATM). The work will focus on several bench marking proteins which have been extensively studied by other techniques to characterize structure and dynamics. Combined with molecular modeling, ATM measurements of photoactive yellow protein (PYP), chicken egg white lysozyme (CEWL) and dihydrofolate reductase (DHFR) and their mutants will identify long range structural motions that impact function. The measurements on PYP will examine if vibrations within the protein backbone enhance chromophore isomerization for photoactive proteins, such as light sensing protein in the eye, rhodopsin. The proposed measurements will determine if collective vibrations overlap the oscillations of the PYP chromophore, and if photocycling is impacted by detuning the frequencies. The measurements will also examine if remote mutations of CEWL and DHFR affect catalytic rates by perturbing the intramolecular dynamics. The PI and co-PI will refine approaches for calculating the isotropic and anisotropic terahertz absorbance of protein solutions and crystals, and develop methods for analysis of the motions corresponding to the observed resonances.