Micromechanical Oscillators for Imaging Molecules by Magnetic Resonance Force Microscopy

9318002加比尼华盛顿大学的乔·加比尼、约翰·赛德斯和加里·德罗布尼最近发表的一系列文章描述了一种对单个分子成像的新方法。所提出的成像技术是基于Stern-Gerlach实验的变体，在该实验中，经典Stern-Gerlach实验中的线性粒子轨迹被微米级机械振荡器的“折叠”轨迹取代。从理论上讲，这种新的磁共振成像方法结合了斯特恩-格拉赫实验的单粒子敏感性、磁共振的非破坏性3D成像能力以及扫描探头技术的亚埃空间分辨率。因此，它可以作为生物分子结构成像技术的基础。最近，IBM Almaden实验室的Dan Rugar和Nino Yannoni报告了第一次用力显微镜手段进行磁共振实验检测。值得注意的是，第一个实验获得了可与最好的室温感应线圈相媲美的室温灵敏度。这项拟议研究的广泛目标是开发实用的仪器，用于对单个生物分子进行原位成像。这种成像技术将是无损的，完全三维的，并将达到亚埃空间分辨率。已发表的理论工作表明，成功的分子成像需要大约10-19N/赫兹的力灵敏度。相比之下，UW/IBM实验中的室温悬臂梁实验表明，其灵敏度为10-15N/Hz。拟议研究的一个目标是利用商业上可获得的悬臂梁获得10-17N/赫兹的灵敏度。在对数尺度上，这代表着朝着开发实用分子成像技术的总体目标前进了一半。正如在本提案正文中所讨论的，可以从以下方面预期灵敏度的显著改善：(1)操作低温(3-10K)，而不是室温，(2)在高真空中操作，而不是毫升真空，(3)从悬臂上去除金金属涂层，(4)从悬臂上烘烤表面污染物，(5)对悬臂材料进行热处理以降低位错密度。我们研究的一个主要重点是做这些实验，这将有助于建立一个可靠的和经过实验验证的对噪声机械振荡器的理解。这一应用知识库将为开发实用的生物分子成像技术奠定必要的基础。我们计划的一个更基本的目标是对微尺度机械振荡器中的噪声机制建立一个可靠的和经过实验验证的理解。这一应用知识库将为开发实用的生物分子成像技术奠定必要的基础。有合理的科学依据可以预期，下一代分子生物学家将照例、快速和容易地获得图像，显示他们正在研究的分子的全部三维结构，并在原位显示它们的所有配体、交联键和糖基化。这种结构成像能力如果能够实现，将通过为解释序列信息提供结构背景，补充和提高现有基因和蛋白质快速测序仪器的价值。我们希望，这将大大加快目前难以治愈的疾病的有效治疗方法的发展。

9318002 Garbini A recent series of articles by Joe Garbini, John Sidles, and Gary Drobny of the University of Washington has described a new method for imaging individual molecules. The proposed imaging technology is based on a variation of the Stern- Gerlach experiment, in which the linear particle trajectories of the classic Stern-Gerlach experiment are replaced by the "folded" trajectory of a micrometer-scale mechanical oscillator. In theory, this new approach to magnetic resonance imaging combines the single-particle sensitivity of the Stern- Gerlach experiment, the nondestructive 3D imaging capability of magnetic resonance, and the subAngstrom spatial resolution of scanning probe techniques. It might therefore serve as the basis of a technology for imaging biomolecular structure. More recently, Dan Rugar and Nino Yannoni of IBM Almaden Laboratories have reported the first experimental detection of magnetic resonance by force microscope means. It is noteworthy that this first experiment achieved a room- temperature sensitivity comparable to the best available room-temperature inductive coils. The broad objective of the proposed research is to develop practical instruments for imaging individual biological molecules in situ. This imaging technology would be nondestructive, fully three-dimensional, and would achieve subAngstrom spatial resolution. Published theoretical work indicates that successful molecular imaging will require a force sensitivity of approximately 10-19 N/Hz. In comparison, the room- temperature cantilever in the UW/IBM experiment experimentally demonstrated a sensitivity of 10-15 N/Hz. One goal of the proposed research is to attain a sensitivity of 10-17N/Hz suing commercially available cantilevers. On a logarithmic scale, this represents progress half-way toward the overall goal of developing a practical molecular imaging technology. As discussed in the body of this proposal, it is reasonable to expect substantial impro vements in sensitivity from: (1) operating a t cryogenic temperatures (3-10K), instead of room temperature, (2) operating in a high vacuum, as opposed to a millitorr vacuum, (3) removing the gold metallic coating from the cantilever, (4) baking surface contaminants off the cantilever, (5) annealing the cantilever material to reduce dislocation density. A primary focus of our research is to do these experiments, which will serve to establish a reliable and experimentally validated understanding of noise mechanical oscillators. This applied knowledge base will serve as the necessary foundation for developing a practical biomolecular imaging technology. A more fundamental objective of our program is to establish a reliable and experimentally validated understanding o noise mechanisms in microscale mechanical oscillators. This applied knowledge base will serve as the necessary foundation for developing a practical biomolecular imaging technology. There reasonable scientific grounds to expect that the next generation o molecular biologist will routinely, quickly, and easily obtain images showing the full three-dimensional structure of the molecules they are studying, in situ, with all their ligands, cross-links, and glycosylation in place. This structural imaging capability, if it can be achieved, will complement and enhance the value of existing instruments for the rapid sequencing of genes and proteins, by providing a structural context for interpretation of sequence information. Our hope is that this will substantially accelerate the development of effective treatments for presently intractable disorders.