INVESTIGATION OF MEMBRANE PROPERTIES TO UNDERSTAND PROTEIN FUNCTION MODULATION

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 生物膜上存在大量具有重要生理功能的蛋白质，包括：泵、通道、载体、受体、酶和能量转换器。蛋白质-脂质相互作用的分子水平的解释是必不可少的，以了解这些膜蛋白的插入，折叠和功能。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。迄今为止，我们已经成功地利用PSC资源，并发现了一些令人兴奋的机制，蛋白质运动的脂质双层和膜的活性调节。我们计算空间变化的自由能分布的可滴定和芳香族蛋白质侧链，连接到模型跨膜段，在整个双层，以确定热力学蛋白质构象变化。我们还量化了由模型跨膜片段的存在引起的双层扰动，以了解疏水性错配（经常被用来解释蛋白质插入，折叠，活性，聚集和脂质微结构域形成的原理）如何驱动蛋白质的稳定性和活性。我们特别希望了解一类重要的膜蛋白的功能，称为离子通道，允许带电分子选择性渗透穿过膜，并与许多神经和心血管疾病。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变化，并了解多不饱和脂质在调节蛋白质活性中的作用。解释双层环境影响的能力对于弥合结构和功能之间的差距是必要的，这将有助于开发特异性药物。

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.