Ultrafast Processes In Proteins And Other Assemblies

描述（由申请人提供）：通过跨膜（TM）螺旋、质子通道、快速折叠蛋白、逆转录酶抑制剂和原纤维中的相关水，通过二维红外光谱（2D IR）获得蛋白质结构随时间变化的残留水平可视化，这是一种强大的新方法。膜蛋白对细胞生理至关重要：它们包括细胞表面受体、离子通道、转运蛋白和氧化还原蛋白。整体膜蛋白介导细胞与细胞外基质之间的双向通讯，构成了高等生物中所有编码序列的四分之一，并且超过一半的商业药物靶向它们。虽然对了解人类健康至关重要，但对它们的3D结构和动力学的了解有限。具有双红外频率的二维红外将测量TM螺旋波动的空间相关性。多肽和蛋白质的同位素标记和腈探针将提高二维红外的空间分辨率，并将其扩展到更大的生物组装。在Gp A的TM部分的界面弱氢键将被检查，以显示键的运动和他们如何稳定螺旋二聚体。二维红外揭示了膜上的空间排列、疏水效应、极性、氢键和埋藏残基之间的其他弱相互作用，揭示了螺旋结合的机制和结构基础。该研究从与病毒感染及其治疗、细胞信号传导和离子动员有关的化学键尺度动力学知识中寻求对生物组装中关键快速过程的分子水平描述。水稳定和优化生命系统的动力学和功能，水与蛋白质和肽相互作用的分子水平动力学描述是理解许多细胞过程的关键。甲型流感病毒原型M2质子通道的微观作用及其突变体如何逃脱抑制，将通过2D IR确定，从而有助于设计针对耐药M2形式的抑制剂。逆转录酶研究将获得HIV酶抑制剂复合物的分子水平知识。淀粉样蛋白原纤维在阿尔茨海默病患者的脑组织中以斑块的形式积累，我们的二维红外实验关注这些原纤维中来自40残基肽A¿40的关键水通道。

DESCRIPTION (provided by applicant): A residue level visualization of protein structures changing with time through associated water in transmembrane (TM) helices, proton channels, fast folding proteins, reverse transcriptase inhibitors and fibrils will be obtained by two dimensional infrared spectroscopy (2D IR) a powerful new method. Membrane proteins are vital to cell physiology: they include cell-surface receptors, ion channels, transporters and redox proteins. Integral membrane proteins mediate bidirectional communication between cells and the extra cellular matrix, compose one-quarter of all coding sequences in higher organisms, and more than half of all commercial drugs target them. Though essential to understanding human health, knowledge of their 3D structures and their dynamics is limited. The 2D IR with dual IR frequencies, will measure spatial correlations in the fluctuations in TM helices. Isotopic labeling of peptides and proteins and nitrile probes will enhance the spatial resolution of 2D IR and extend it to larger biological assemblies. Weak hydrogen bonds at the interfaces of TM sections of Gp A will be examined to show the bond motions and how they stabilize helix dimers. 2D IR exposes spatial arrangements across the membrane, hydrophobic effects, polarity, hydrogen bonding and other weak interactions between buried residues that enlighten the mechanisms and structural basis of helix association. The research seeks a molecular level description of key fast processes in biological assemblies from a chemical bond scale dynamics knowledge pertaining to viral infections and their therapy, cellular signaling and ion mobilization. Water stabilizes and optimizes the dynamics and functionality of living systems and a molecular level description of the dynamics of water interacting with proteins and peptides is key to understanding many cellular processes The microscopic action of a prototype M2 proton channel from Influenza A virus and how its mutants can escape inhibition, will be determined by 2D IR thereby contributing to the design of inhibitors targeting drug-resistant forms of M2. The reverse transcriptase research will acquire molecular level knowledge of HIV enzyme-inhibitor complexes. Amyloid fibrils accumulate as plaques in the brain tissue of Alzheimer's patients and our 2D IR experiments concern key water channels in these fibrils from the 40-residue peptide A¿40.