Correlated Motions of Folded and Non-Folded Proteins by NMR Spectroscopy and Computation

通过核磁共振波谱和计算研究折叠和非折叠蛋白质的相关运动

• 批准号: 0621482
• 负责人: Rafael Bruschweiler
• 金额: $ 41.12万
• 依托单位: Florida State University
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0621482&HistoricalAwards=false
• 关键词: Correlated; Motions; Folded; Non; Proteins

Detailed information on protein dynamics at an atomic level is of fundamental biophysical importance for understanding protein stability and function. The overall goal of this research is the exploration and development of new methods for a comprehensive description of complex dynamics of folded and non-folded protein systems and to demonstrate their applicability to biologically important systems. Natively unfolded proteins play a vital role in a wide range of biophysical and biochemical processes. Recent analysis of NMR residual dipolar coupling measurements of unfolded proteins suggest that these states can be well characterized by conformational ensembles that are locally biased in their backbone dihedral angles as a function of the amino-acid types. This project will analyze a large variety of such ensembles by statistical methods that assess the internal translational and reorientational correlation behavior. This analysis will be linked to dynamic NMR parameters and thermodynamic properties. Comparison with the folded state behavior will give useful insights into determinants of protein stability. Motional modes in proteins often exhibit a collective character. The nature of these motions and their entropic implications will be explored in view of recent experimental NMR residual dipolar coupling and relaxation data as well as advances in conformational sampling methods and simplified descriptions in terms of reorientational elastic network models. NMR experiments will be performed on the protein MDM2 and its interactions with other polypeptides. This project will produce new computational, statistical mechanical, and NMR spectroscopic concepts for the characterization of folded and non-folded protein states, which will enhance the understanding of protein behavior and function and serve as input for the engineering of proteins with new properties. The project will provide interdisciplinary training and research opportunities for graduate students and postdoctoral researchers, including students from demographically underrepresented groups, including female, African-American, Native American Indian, Hispanic, and (US) Asian/Pacific Islander graduate students. Research methods and results will be incorporated into advanced undergraduate and graduate courses on biophysics and biomolecular spectroscopy. The PI will participate in NHMFL's strong outreach programs for high school and junior college students and a summer undergraduate research program. This project is jointly supported by Molecular Biophysics in the Division of Molecular and Cellular Biosciences in the Directorate for Biological Sciences and the Experimental Physical Chemistry Program in the Division of Chemistry in the Mathematical and Physical Sciences Directorate.

在原子水平上关于蛋白质动力学的详细信息对于理解蛋白质的稳定性和功能具有基本的生物物理重要性。这项研究的总体目标是探索和开发新的方法来全面描述折叠和非折叠蛋白质系统的复杂动力学，并证明它们对生物重要系统的适用性。天然未折叠蛋白质在广泛的生物物理和生化过程中起着至关重要的作用。最近对未折叠蛋白质的核磁共振剩余偶极耦合测量结果的分析表明，这些状态可以很好地用构象系综来描述，这些构象系综随氨基酸类型的变化而在其主干二面角上局部偏向。这个项目将通过评估内部平移和重新定位相关行为的统计方法来分析大量这样的集合。这一分析将与动态核磁共振参数和热力学性质联系起来。与折叠状态行为的比较将对蛋白质稳定性的决定因素提供有用的见解。蛋白质中的运动模式通常表现出集体性。鉴于最近的核磁共振剩余偶极耦合和弛豫实验数据，以及构象采样方法的进展和重定向弹性网络模型的简化描述，将探讨这些运动的性质和它们的熵含义。将对MDM2蛋白及其与其他多肽的相互作用进行核磁共振实验。该项目将产生新的计算、统计力学和核磁共振波谱概念，用于表征折叠和非折叠的蛋白质状态，这将增强对蛋白质行为和功能的理解，并为具有新性质的蛋白质的工程提供输入。该项目将为研究生和博士后研究人员提供跨学科培训和研究机会，包括来自人口代表性不足群体的学生，包括女性、非裔美国人、美洲原住民、西班牙裔和(美国)亚洲/太平洋岛民研究生。研究方法和成果将纳入生物物理学和生物分子光谱学的高级本科生和研究生课程。PI将参与NHMFL针对高中生和大专学生的强有力的外展计划，以及夏季本科生研究计划。该项目由生物科学局分子和细胞生物科学部的分子生物物理学和数学和物理科学局化学部的实验物理化学计划共同支持。