Multidimensional Femtosecond Correlation Spectroscopic Probes of Biomolecules

生物分子多维飞秒相关光谱探针

• 批准号: 7988243
• 负责人: SHAUL MUKAMEL
• 金额: $ 27.06万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-01 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7988243
• 关键词: Affect; Algorithms; Alzheimer' s Disease; Amides; Amyloid; Amyloid Fibrils; Arts; Binding; Biological; Catalysis; Cell membrane; Cells; Cellular Membrane; Charge; Communities; Complex; Coupling; Deposition; Development; Discrimination; Disease; Electronics; Electrostatics; Environment; Extravasation; Frequencies; Generations; Growth; Guidelines; Health; Human; Huntington Disease; Hydrogen Bonding; Kinetics; Knowledge; Lasers; Lipids; Measures; Membrane; Membrane Proteins; Methodology; Molecular; Monitor; Motion; Neurodegenerative Disorders; Non-Insulin-Dependent Diabetes Mellitus; Optics; Parkinson Disease; Pattern; Peptides; Permeability; Phospholipids; Physiologic pulse; Prion Diseases; Proteins; Relaxation; Research; Resolution; Role; Shapes; Side; Signal Transduction; Simulate; Structure; Sum; Surface; System; Techniques; Technology; Testing; Time; Tissues; Toxic effect; Vertebral column; Water; amyloid peptide; cell injury; design; effective therapy; human disease; improved; large scale simulation; novel; polypeptide; programs; protein aggregate; protein misfolding; public health relevance; research study; response; simulation; tool; two-dimensional; ultraviolet; vibration

DESCRIPTION (provided by applicant): The formation and deposition of amyloid fibrils is associated with more than 20 neurodegenerative diseases. These include Alzheimer's, Parkinson's, Huntington's diseases, and the transmissible spongiform encephalopathies and type II diabetes. Oligomeric or other prefibrillar precursors of the fibrils are believed to be the main toxic species, but the mechanism of cell and tissue damage in amyloid-related diseases is not well understood. Improvement of our knowledge of the structure, kinetics of amyloidogenic polypeptides, and of their toxicity is essential for the development of effective treatments of amyloid disorders. Coherent multidimensional optical techniques provide novel probes into the fibril fluctuating structure through the response of molecular vibrational and electronic motions to sequences of carefully timed and shaped femtosecond laser pulses ranging from the infrared to the ultraviolet. Simulation techniques aimed at the design and interpretation of these multidimensional optical signals will be developed. Chirality-induced signals obtained by optimizing the pulse polarization configurations and shapes enhance the resolution and reveal fine details. Cross-peak patterns between side-chain vibrations or electronic excitations of aromatic side-chains with the protein backbone protein/membrane interfaces will be predicted in two-dimensional (2D) UV. Strategies for disentangling multidimensional spectra, enhancing the resolution, and amplifying desired features will be developed. The optical response will be used to characterize small oligomers and their kinetics in the formation of fibrils. Discrimination by their size and structure is of fundamental importance for understanding the molecular factors that affect their formation. It has been suggested that the interactions of amyloidogenic polypeptides with the cell membrane can accelerate fibril formation and are involved in the toxicity of oligomers or protofibrils. Amyloid peptides aggregate on the lipid surface penetrate into membranes and alter their permeability, which may contribute to cell damage. The nonlinear optical probes developed in this program can directly monitor how the formation of fibrils on a membrane damages the bilayer's integrity. Interface-specific even-order optical techniques will be designed to study aggregates of amyloidogenic polypeptides on membranes and identify spectroscopic signatures of their toxicity. PUBLIC HEALTH RELEVANCE: The structure, kinetics, and aggregation mechanism of misfolded proteins which form amyloid fibrils and are associated with several human diseases will be investigated through their response to sequences of ultrashort infrared and UV optical pulses. Surface specific technique will be applied for probing the toxicity of fibrils on membranes. Simulation techniques for probing the binding, fluctuations, and motions of biomolecular complexes will be developed.

描述(申请人提供)：淀粉样蛋白纤维的形成和沉积与20多种神经退行性疾病有关。这些疾病包括阿尔茨海默氏症、帕金森氏症、亨廷顿氏症，以及传染性海绵状脑病和II型糖尿病。纤维的寡聚体或其他前纤维前体被认为是主要的毒性物种，但淀粉样蛋白相关疾病中细胞和组织损伤的机制尚不清楚。提高我们对淀粉样多肽的结构、动力学及其毒性的了解对于开发有效的淀粉样变性疾病的治疗方法是至关重要的。相干多维光学技术通过分子振动和电子运动对从红外到紫外线范围内精心计时和整形的飞秒激光脉冲序列的响应，为研究纤维波动结构提供了新的探针。将开发旨在设计和解释这些多维光学信号的模拟技术。通过优化脉冲偏振构型和形状得到的手性诱导信号提高了分辨率并揭示了细节。在二维(2D)紫外光中，可以预测芳香族侧链与蛋白质骨架蛋白/膜界面的侧链振动或电子激发之间的交叉峰型。将开发解开多维光谱的纠缠、提高分辨率和放大所需特征的策略。光学响应将被用来表征小分子齐聚物及其在形成纤维过程中的动力学。区分它们的大小和结构对于理解影响它们形成的分子因素是至关重要的。已有研究表明，致淀粉样多肽与细胞膜的相互作用可以加速纤维的形成，并参与低聚体或原纤维的毒性作用。淀粉样多肽聚集在脂质表面，穿透到膜中，改变其通透性，这可能导致细胞损伤。在这个项目中开发的非线性光学探头可以直接监测膜上纤维的形成如何损害双层的完整性。界面特定的偶数阶光学技术将被设计来研究膜上产生淀粉样多肽的聚集体，并识别其毒性的光谱特征。 与公众健康相关：错误折叠的蛋白质形成淀粉样纤维，并与几种人类疾病有关，将通过它们对超短红外和紫外光脉冲序列的响应来研究它们的结构、动力学和聚集机制。表面特异性技术将被应用于探测纤维对膜的毒性。将开发用于探测生物分子复合体的结合、波动和运动的模拟技术。