Ultrafast Processes In Proteins And Other Assemblies

蛋白质和其他组装体中的超快过程

• 批准号: 8102903
• 负责人: ROBIN Main HOCHSTRASSER
• 金额: $ 28.9万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 1977
• 资助国家: 美国
• 起止时间: 1977-02-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8102903
• 关键词: Alzheimer' s Disease; Amantadine; Amides; Amyloid Fibrils; Binding; Biological; Biophysics; Cell Surface Receptors; Cell physiology; Cells; Charge; Chemicals; Code; Collagen; Communication; Complex; Coupled; Cytoskeleton; Dependence; Dependency; Drug Delivery Systems; Drug resistance; Elements; Enzyme Inhibitor Drugs; Enzyme Inhibitors; Enzymes; Equilibrium; Frequencies; HIV; HIV-1; Health; Human; Hydration status; Hydrogen Bonding; Imagery; Individual; Influenza; Influenza A virus; Integral Membrane Protein; Ion Channel; Ions; Kinetics; Knowledge; Label; Lipids; Location; Measurement; Measures; Mediating; Membrane; Membrane Proteins; Methods; Microscopic; Modeling; Molecular; Molecular Conformation; Motion; Nitriles; Organism; Oxidation-Reduction; Patients; Peptides; Pharmaceutical Preparations; Population; Positioning Attribute; Potential Energy; Process; Proteins; Protons; RNA-Directed DNA Polymerase; Research; Resolution; Reverse Transcriptase Inhibitors; Role; Scanning; Signal Transduction; Site; Structure; Surface; System; Temperature; Time; Tryptophan; Variant; Virus Diseases; Water; Work; base; big gastrin; brain tissue; chemical bond; design; dimer; flexibility; improved; infrared spectroscopy; inhibitor/antagonist; mutant; novel; protein folding; protein structure; prototype; public health relevance; research study; response; simulation; three dimensional structure; two-dimensional; water channel

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. PUBLIC HEALTH RELEVANCE: The work provides a bond scale knowledge of influenza viral infections and therapy, protein assembly and signal transduction, cell-surface receptors and ion channels. A molecular level knowledge of enzyme-inhibitors for HIV treatments and amyloid fibrils associated with Alzheimer's disease form another focus of this work.

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，蛋白质结构随时间变化的残留水平可视化将通过二维红外光谱（2D IR）获得，这是一种强大的新方法。膜蛋白对细胞生理学至关重要：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。整合膜蛋白介导细胞和细胞外基质之间的双向通讯，构成高等生物体中所有编码序列的四分之一，并且超过一半的商业药物都以它们为目标。尽管对于了解人类健康至关重要，但对其 3D 结构及其动力学的了解却很有限。具有双红外频率的 2D IR 将测量 TM 螺旋波动的空间相关性。肽和蛋白质以及腈探针的同位素标记将增强 2D IR 的空间分辨率，并将其扩展到更大的生物组件。将检查 Gp A TM 部分界面处的弱氢键，以显示键运动以及它们如何稳定螺旋二聚体。 2D IR 揭示了跨膜的空间排列、疏水效应、极性、氢键和埋藏残基之间的其他弱相互作用，揭示了螺旋缔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相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。水可以稳定和优化生命系统的动力学和功能，对水与蛋白质和肽相互作用的动力学的分子水平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 M2 耐药形式的抑制剂。逆转录酶研究将获得 HIV 酶抑制剂复合物的分子水平知识。淀粉样原纤维在阿尔茨海默病患者的脑组织中积聚为斑块，我们的 2D IR 实验关注这些原纤维中来自 40 个残基肽 A¿40 的关键水通道。 公共卫生相关性：这项工作提供了流感病毒感染和治疗、蛋白质组装和信号转导、细胞表面受体和离子通道的债券规模知识。用于艾滋病毒治疗的酶抑制剂和与阿尔茨海默病相关的淀粉样原纤维的分子水平知识构成了这项工作的另一个重点。