Single-Molecule Scanning Tunneling Spectroscopy of Surface-Tethered Proteins

表面束缚蛋白的单分子扫描隧道光谱

基本信息

项目摘要

DESCRIPTION (provided by applicant): The scanning tunneling microscope routinely provides atomic-resolution imaging and spectroscopic measurements of single molecules on surfaces. The primary obstacle preventing the full power of this capability from being applied to biological targets such as proteins is the limitation that, in general, electrons cannot tunnel through more than 2 nm of an insulating material. This restriction impacts entire classes of biologically interesting samples such as proteins (typically ~5 nm diameter) and lipid bilayers (~6 nm thickness). This proposal describes the development of instrumentation and methodologies expanding the sub- nanometer imaging capabilities of scanning tunneling microscopy (STM) to biologically important single molecules and biomolecule assemblies on surfaces, including proteins embedded in lipid membranes. In particular, this approach will allow direct observations and structural studies of G protein-coupled receptor (GPCR)-ligand complexes, which are the targets of over half of all commercially available drugs, and are not possible to visualize directly using other techniques. This work will utilize an alternating-current STM (AC-STM) that circumvents the conductivity requirement by measuring the tunneling current as an alternating bias is applied to the sample at frequencies from 0.5-20 GHz. The tunneling current has been shown to scale with surface polarizability or capacitance, providing spectroscopic as well as topographic information about molecules in the tunneling junction. This technique can be applied to make sub-nanometer topographic and spectroscopic measurements of biomolecules on surfaces. This proposal specifically aims to characterize two types of proteins on surfaces as representative examples of two classes of protein targets: 1) the copper redox protein P. aeruginosa azurin, as a model for the class of metalloproteins, 2) serotonin 5-HT1 receptor proteins specifically bound to their ligand on a surface, as models for GCPRs and other membrane-associated proteins, and as a demonstration of the ability to correlate structure with ligand-binding properties. Relevance: The ability to image the structures of single biomolecules such as proteins would have major implications for medical science ranging from disease diagnosis to drug discovery. This proposal describes the development of instrumentation and methodology that will enable structural information to be extracted from single molecules on surfaces. This capability will be applied to proteins embedded in lipid bilayers, which are the targets of over 50% of all modern drugs, and which are difficult to analyze by other means.
描述(由申请人提供):扫描隧道显微镜常规提供表面单分子的原子分辨率成像和光谱测量。将这种能力的全部力量应用于诸如蛋白质之类的生物目标的主要障碍是,一般来说,电子不能穿过超过2纳米的绝缘材料。这一限制影响了整个生物上有趣的样品类别,如蛋白质(通常直径约5纳米)和脂质双层(厚度约6纳米)。本提案描述了仪器和方法的发展,将扫描隧道显微镜(STM)的亚纳米成像能力扩展到表面上重要的生物单分子和生物分子组件,包括嵌入在脂质膜中的蛋白质。特别是,这种方法将允许G蛋白偶联受体(GPCR)-配体复合物的直接观察和结构研究,这是超过一半的市售药物的靶标,并且不可能使用其他技术直接可视化。这项工作将利用交流STM (AC-STM),当在0.5-20 GHz频率范围内对样品施加交流偏置时,通过测量隧道电流来绕过电导率要求。隧穿电流已被证明与表面极化率或电容成比例,提供了关于隧穿结分子的光谱和地形信息。该技术可用于表面生物分子的亚纳米形貌和光谱测量。本提案特别旨在表征表面上两种类型的蛋白质,作为两类蛋白质靶点的代表性例子:1)铜氧化还原蛋白P. aeruginosa azurin,作为金属蛋白类的模型;2)表面上特异性结合其配体的5-羟色胺5-HT1受体蛋白,作为GCPRs和其他膜相关蛋白的模型,并作为结构与配体结合特性相关能力的证明。相关性:对单个生物分子(如蛋白质)结构成像的能力将对从疾病诊断到药物发现的医学科学产生重大影响。本提案描述了仪器和方法的发展,这些仪器和方法将能够从表面上的单个分子中提取结构信息。这种能力将应用于嵌入脂质双分子层的蛋白质,这些蛋白质是超过50%的现代药物的靶标,而且很难用其他方法分析。

项目成果

期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
From the bottom up: dimensional control and characterization in molecular monolayers.
  • DOI:
    10.1039/c2cs35365b
  • 发表时间:
    2013-04-07
  • 期刊:
  • 影响因子:
    46.2
  • 作者:
    Claridge SA;Liao WS;Thomas JC;Zhao Y;Cao HH;Cheunkar S;Serino AC;Andrews AM;Weiss PS
  • 通讯作者:
    Weiss PS
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Shelley Ann Claridge其他文献

Shelley Ann Claridge的其他文献

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{{ truncateString('Shelley Ann Claridge', 18)}}的其他基金

Nanostructured Hydrogel Surfaces for Artificial Extracellular Matrix
用于人工细胞外基质的纳米结构水凝胶表面
  • 批准号:
    10373590
  • 财政年份:
    2022
  • 资助金额:
    $ 5.3万
  • 项目类别:
Nanostructured Hydrogel Surfaces for Artificial Extracellular Matrix
用于人工细胞外基质的纳米结构水凝胶表面
  • 批准号:
    10705022
  • 财政年份:
    2022
  • 资助金额:
    $ 5.3万
  • 项目类别:
Single-Molecule Scanning Tunneling Spectroscopy of Surface-Tethered Proteins
表面束缚蛋白的单分子扫描隧道光谱
  • 批准号:
    7928338
  • 财政年份:
    2009
  • 资助金额:
    $ 5.3万
  • 项目类别:
Single-Molecule Scanning Tunneling Spectroscopy of Surface-Tethered Proteins
表面束缚蛋白的单分子扫描隧道光谱
  • 批准号:
    7991338
  • 财政年份:
    2009
  • 资助金额:
    $ 5.3万
  • 项目类别:

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