Spectroscopic Study of Protein Folding Dynamics

蛋白质折叠动力学的光谱研究

• 批准号: 8299545
• 负责人: FENG GAI
• 金额: $ 30.99万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8299545
• 关键词: Address; Affect; Amino Acids; Binding; Biological; Biological Models; Communities; Complex; Crowding; Cystic Fibrosis; Development; Disease; Electron Transport; Elements; Environment; Event; Fluorescence; Fluorescence Resonance Energy Transfer; Funding; Goals; Helix-Turn-Helix Motifs; Hydration status; Influenza A virus; Ion Channel; Kinetics; Lead; Mediating; Membrane; Membrane Proteins; Methods; Molecular; Neurodegenerative Disorders; Nitriles; Pathway interactions; Peptides; Process; Property; Protein Binding; Proteins; Protons; Psychological Techniques; Public Health; Research; Resolution; Role; Series; Solutions; Spectrum Analysis; Structure; System; Techniques; Tertiary Protein Structure; Time; Work; aqueous; base; design; improved; insight; macromolecule; novel; polypeptide; protein aggregation; protein folding; protein function; research study; structural biology; success

DESCRIPTION (provided by applicant): Proteins acquire their unique functions through specific folding of their linear polypeptide chains. Misfolding results in numerous diseases, such as cystic fibrosis and various neurodegenerative disorders. Although a great deal of work has been done to investigate how the secondary and tertiary structures of proteins are formed and both experimental and theoretical techniques for studying protein folding are continually becoming more refined, a quantitative and predictive understanding of protein folding is still not attainable. There are still many fundamental questions, such as: How do specific and nonspecific interactions with the surroundings determine the folding pathways, the roughness of the energy landscape, and the thermally and kinetically accessible conformational substrates? On what range of timescales do particular conformational and folding events occur in crowded environments and/or membranes? Addressing these questions presents the need for further studies with time-resolved spectroscopic techniques that can provide the necessary time resolution and structural sensitivities. The principal objective of the proposed research is therefore to develop new spectroscopic methods and new conformational probes that can be used to generate detailed structural interpretations of the transient folding species and their dynamics over a wide range of timescales. A comprehensive set of experiments are planned to gain new insight into the understanding of various aspects of the protein folding problem, as well as the structure-dynamics-function relationship of membrane proteins. The technical goals are to: (a) develop new spectroscopic probes and methods for protein folding and binding studies; (b) investigate how macromolecular crowding and confinement affect the kinetics of protein folding and aggregation; (c) study the early kinetic events in membrane protein folding; (e) probe the conformational dynamics underlying membrane protein function. Achieving these specific aims should result in not only new experimental methods for various biological applications, but also new findings that would help improve our understanding of many fundamental issues in protein folding, thus making practical and direct contributions to the field.

描述（由申请人提供）：蛋白质通过其线性多肽链的特定折叠获得其独特的功能。错误折叠会导致许多疾病，例如囊性纤维化和各种神经退行性疾病。尽管人们已经做了大量的工作来研究蛋白质的二级和三级结构是如何形成的，并且研​​究蛋白质折叠的实验和理论技术不断变得更加完善，但仍然无法实现对蛋白质折叠的定量和预测性理解。仍然存在许多基本问题，例如：与周围环境的特异性和非特异性相互作用如何决定折叠路径、能量景观的粗糙度以及热和动力学可接近的构象基质？在拥挤的环境和/或膜中特定的构象和折叠事件发生在什么时间尺度范围内？解决这些问题需要利用时间分辨光谱技术进行进一步研究，以提供必要的时间分辨率和结构敏感性。因此，拟议研究的主要目标是开发新的光谱方法和新的构象探针，可用于对瞬态折叠物种及其在广泛的时间尺度上的动力学产生详细的结构解释。计划进行一系列全面的实验，以获得对蛋白质折叠问题各个方面以及膜蛋白的结构-动力学-功能关系的新见解。技术目标是： (a) 开发用于蛋白质折叠和结合研究的新光谱探针和方法； (b) 研究大分子拥挤和限制如何影响蛋白质折叠和聚集的动力学； (c) 研究膜蛋白折叠的早期动力学事件； (e) 探测膜蛋白功能的构象动力学。实现这些具体目标不仅应该为各种生物应用带来新的实验方法，而且应该带来新的发现，有助于提高我们对蛋白质折叠中许多基本问题的理解，从而为该领域做出实际和直接的贡献。