INVESTIGATION OF MEMBRANE PROPERTIES TO UNDERSTAND PROTEIN FUNCTION MODULATION

研究膜特性以了解蛋白质功能调节

• 批准号: 7723155
• 负责人: TONI ALLEN
• 金额: $ 0.05万
• 依托单位: CARNEGIE-MELLON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7723155
• 关键词: Biological; Cardiovascular Diseases; Charge; Class; Computer Retrieval of Information on Scientific Projects Database; Development; Environment; Enzymes; Free Energy; Funding; Grant; Institution; Investigation; Ion Channel; Lipid Bilayers; Lipids; Mechanics; Membrane; Membrane Proteins; Microscopic; Modeling; Molecular; Movement; Neurologic; Pharmaceutical Preparations; Physiological; Play; Potassium Channel; Property; Proteins; Pump; Regulation; Research; Research Personnel; Resources; Role; Side; Simulate; Source; Structure; Techniques; Thermodynamics; Transducers; United States National Institutes of Health; numb protein; protein function; receptor; simulation; success

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Biological membranes play host to a large number of the proteins with vital physiological roles, including: pumps, channels, carriers, receptors, enzymes and energy transducers. A molecular-level interpretation of protein-lipid interactions is essential to understand the insertion, folding and function of these membrane proteins. Microscopic simulation, combined with advanced statistical mechanical techniques, can assist in uncovering some hidden microscopic mechanisms. We have had much success using PSC resources to date and have uncovered some exciting mechanisms of protein movement in lipid bilayers and membrane regulation of activity. We calculate spatially varying free energy profiles of titratable and aromatic protein side-chains, attached to model transmembrane segments, throughout the bilayer to determine the thermodynamics governing protein conformational changes. We are also quantifying bilayer perturbations induced by the presence of model transmembrane segments to understand how hydrophobic mismatch (a principle frequently summoned to explain protein insertion, folding, activity, aggregation and lipid micro-domain formation) drives protein stability and activity. We particularly wish to understand the function of an important class of membrane proteins known as ion channels which allow selective permeation of charged molecules across the membrane and are associated with many neurological and cardiovascular disorders. We are simulating membranes of different composition around the KcsA potassium channel to investigate experimentally observed changes in protein activity and to understand the roles of polyunsaturated lipids in regulating protein activity. The ability to explain the influence of the bilayer environment is necessary to bridge the gap between structure and function and which will aid the development of specific drugs.

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 生物膜是许多具有重要生理作用的蛋白质的宿主，包括泵、通道、载体、受体、酶和能量传导器。蛋白质-脂质相互作用的分子水平解释对于理解这些膜蛋白的插入、折叠和功能是必不可少的。微观模拟与先进的统计力学技术相结合，可以帮助揭示一些隐藏的微观机制。到目前为止，我们已经成功地利用了PSC资源，并发现了一些令人兴奋的蛋白质在脂双层中运动的机制和膜对活性的调节。我们计算可滴定和芳香蛋白质侧链的空间变化的自由能分布，这些侧链附着在模型跨膜片段上，在整个双层中，以确定控制蛋白质构象变化的热力学。我们还在量化模型跨膜片段的存在引起的双层扰动，以了解疏水错配(这一原理经常被用来解释蛋白质的插入、折叠、活性、聚集和脂质微域的形成)如何驱动蛋白质的稳定性和活性。我们尤其希望了解一类重要的膜蛋白的功能，即离子通道，它允许带电分子选择性地穿透细胞膜，与许多神经和心血管疾病有关。我们正在模拟KCSA钾通道周围不同组成的膜，以研究实验观察到的蛋白质活性的变化，并了解多不饱和脂类在调节蛋白质活性中的作用。能够解释双层环境的影响对于弥合结构和功能之间的差距是必要的，这将有助于特定药物的开发。