This study addresses three unmet needs: 1) development of widely accessible native mass spectrometry (MS) methods and 2) native top-down mass spectrometry (TDMS) methods for high flow sources on an Agilent Q-TOF mass spectrometer, and 3) confirming suitability of structures for lossless ion manipulation (SLIM) ion mobility (IM) MS methods for analysis of native intact proteins. To decrease the cost and training barrier to performing MS, TDMS, and IM-MS analysis of native proteins, we have developed methods for nanospray, microspray, and heated high flow electrospray ionization sources. SLIM offers the highest full-scan IM resolution available, but commercial instrumentation has not previously been applied to native MS. Our optimized methods extend the upper m/z limit beyond the manufacturer’s default IM mode upper mass limit of 4000 m/z to 7000 m/z, which allows for intact protein and native MS analysis of a variety of proteins, including native MS of intact IgG antibodies. Using the robust and facile Agilent Jet Spray (AJS) source, we demonstrate the application of native protein MS to amyotrophic lateral sclerosis (ALS)-associated Cu/Zn-superoxide dismutase proteoforms, characterizing a novel conformer and quaternary structural changes.