Development of a Mega-Dalton Mass Spectrometer for Biological Research

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This award supports the development of a mass spectrometer capable of mass analyzing mega-Dalton biomolecules with unprecedented sensitivity at Carnegie Mellon University. State-of-the-art mass spectrometers currently lack the combined sensitivity, resolution and mass accuracy necessary for routine analysis of singly-charged high molecular weight ions. This next-generation matrix-assisted laser desorption ionization (MALDI) ion trap mass spectrometer will be designed to overcome the high m/z (mass/charge) barrier. The project incorporates a cross-disciplinary collaborative effort by chemists, physicists and biologists both in academia and industry and should greatly impact the mass analysis of mega-Dalton biomolecules. The proposed heavy-ion mass spectrometer will have ultra-high sensitivity by interfacing three innovative MS components: i.) a unique MALDI source, ii.) a mega-Dalton mass range ion trap and iii.) a detector with 100% detection efficiency at high mass. The goal is to analyze large molecules or complexes with m/z ranging from 10,000 to 15,000,000 at the attomole level. The development of this new instrument should provide breakthrough performance for the direct mass analysis of mega-Dalton biomolecules, bio-structures, non-covalent and covalent multi-protein complexes, protein/adducts, DNA and viruses. This project is directed at a long-term research goal of single cell proteomics. The development and dissemination of a next-generation mass spectrometer for analysis of macromolecules will impact many fields. For the biological sciences, the proposed instrument should significantly advance research in proteomics, where the challenge is to identify all proteins and characterize all protein-protein interactions in a biological system. In addition, the instrument's capabilities should benefit the field of nanotechnology, which currently lacks a good method to characterize large molecules. To educate students and scientists about the heavy-ion mass spectrometer, presentations about this development will target both small colleges and major universities. The mega-Dalton mass spectrometer will be used to teach undergraduates, graduate students and post doctorial students about MS instrumentation development both in these presentations and in courses taught at Carnegie Mellon (Chem 09-543: Mass Spectrometry and Chem 09-445: Undergraduate Research). Undergraduate research positions will be offered to students from under-represented groups. To widen the impact to the greatest number of students, the development of the new spectrometer will be incorporated into a NSF Internet educational tool called the Virtual Mass Spectrometry Laboratory (http://svmsl.chem.cmu.edu).