UC Berkeley

Mass spectrometry (MS) is a ubiquitous method in analytical science, with applications ranging from physics to molecular biology. The fundamental nature of mass makes weighing molecules and/or their fragments a reliable way to characterize identity, structure, and function. Conventional MS methods work by measuring the mass to charge ratio (m/z) of an ensemble of ionized analyte molecules. The mass is then determined by multiplying the m/z by the charge (z) of the ion, a quantity that is typically determined either by ionization method or by measuring the spacing between m/z peaks. For smaller molecules, deconvolving the charge from the m/z spectrum is straightforward, but becomes increasingly difficult for large molecules (>1 MDa) or samples that contain heterogeneous mixtures because m/z peaks overlap and are unresolved. Single ion MS techniques circumvent this problem by measuring the mass of individual ions via independent measurements of both the m/z and the charge, but these measurement methods are typically too time-consuming to be practical for acquiring the thousands of ions necessary to produce meaningful mass spectrum. This dissertation focuses on the development and application of multiplexed charge detection mass spectrometry (CDMS), a single ion MS technique that enables much faster individual ion mass measurements. A novel data analysis method that uses the amplitudes of the first and second harmonic frequencies in the Fourier transform of ion signal to dynamically determine ion energies is demonstrated. By monitoring the ion energies of individually trapped ions in CDMS, information about ion cross section and neutral solvent evaporation is obtained. For the first time, multiplexed CDMS measurements are demonstrated and the time necessary to acquire a statistically significant sample of individual ion data is decreased by an order of magnitude compared to other CDMS techniques. Simulations of optimized CDMS data show that multiplexed measurements combined with a novel method for decoupling ion m/z and frequency can further decrease the ion acquisition time to less than one minute. These CDMS techniques are applied to the study of the mechanisms of electrospray ionization for nanometer-sized droplets and macromolecules originating from different aqueous solutions and new insights on these previously difficult to measure systems are gained.