Toward Single-Molecule Nanomechanical Mass Spectrometry

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DESCRIPTION (provided by applicant): Mass spectrometry (MS) is emerging as one of the most important tools for proteomics. Modern MS protocols, recently developed for identification of low concentration analytes in the presence of very large backgrounds, have been central to many important advances in systems biology. However, these protocols are accompanied with important limitations, especially in terms of their sensitivity and ease of methodology. Advances emerging from nanoscience may offer new approaches to MS. Recently, using nanoelectromechanical systems (NEMS) in vacuo, the proposers have demonstrated mass sensing at the 7 zeptogram level -- the mass of an individual 4 kilodalton molecule. This represents a million-fold improvement over the most recent state-of-the-art laboratory demonstrations using microscale devices, and a billion-fold improvement over commercial devices. Yet the work is still in its infancy; significant further improvements with NEMS are imminent. In this initial (R21) effort, the proposers will make the crucial initial steps to transform this advance in nanoscience into a real technology that is directly applicable to biological mass spectrometry. A significant amount of research will now be required to transform this unprecedented mass sensitivity into a usable and efficient new form of MS. Realizing this transformation is the principal focus and intent of the proposed work. NEMS-MS offers the promise of sensitivity down to the single-molecule level. A new single-molecule, NEMS-based mass spectrometry (NEMS-MS) would enable powerful new assays utilizing extremely minute amounts of precious/rare analyte. In contrast to genomics research -- where gene amplification can produce large amounts of identical analytes enabling more "conventional" MS protocols -- extreme sensitivity is crucial for proteomics. If successful, this exploratory program will provide benchmark demonstrations of single-molecule mass sensing, chart a methodical course toward the realization of single-molecule mass spectrometry for proteomics, and assemble a next-phase effort (R01) for the full realization of this vision. The collaborative team includes some of the forefront practitioners of proteomic-based mass spectrometry, of nanodevice physics and microfluidics, and of novel surface chemistry approaches to MS.