This proposal describes a program for developing gas-phase ion separation strategies for the analysis of complex biomolecular mixtures such as combinatorial libraries. Preliminary data show that a new ion mobility/time-of-flight mass spectrometry technique combined with electrospray ionization allows components of complex peptide mixtures to be simultaneously characterized. Th this approach the components of the mixture are ionized and the ions are separated by differences in their mobilities through an inert buffer gas before being dispersed into a mass spectrometer. The gas-phase separation step allows structural and sequence isomers to be distinguished. An important feature of the proposal is the development of instrumentation that is capable of parallel sequencing of multiple mobility-separated components of a mixture. This is feasible because fragment ions will be formed after mobility separation and thus are labeled according to parent ion mobilities. Applications of the proposed techniques to several types of libraries (peptide, oligonucleotide, and organic molecule) are outlined. The ability to characterize isomers within a given m/z ratio will have a tremendous impact on the utility of mass spectrometric methods in revealing whether or not expected library components are truly present. This will be a powerful tool in refinement of synthetic methods, and will provide opportunities for development of new search strategies.
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