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Multiplexed Charge Detection Mass Spectrometer for Extended Mass and Collisional Cross Section Measurements

Award Number: R01GM139338
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/22/2020
PERIOD OF PERFORMANCE END DATE: 05/31/2030

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Multiplexed Charge Detection Mass Spectrometer for Extended Mass and Collisional Cross Section Measurements - Project Summary Large biomolecular assemblies constitute much of the molecular machinery necessary for cellular function and are often targeted by therapeutics. Other large molecular assemblies, including virus-like particles, lipid nanoparticles, and some large synthetic particles are used as drug delivery agents. These molecular assembles are large (masses in the range of MDa to GDa) and heterogeneous, making them challenging to accurately analyze using conventional analytical methods. Electrospray ionization can transfer these large complexes intact into the gas phase, but both the high mass and heterogeneity prevents analysis using conventional mass spectrometers due to overlapping and unresolved charge states. Charge detection mass spectrometry (CDMS) weighs individual ions, circumventing interference between charge states and has been used to analyze heterogeneous complexes with masses up to a GDa. However, individual ion measurements can be slow, typically requiring minutes to hours to analyze a sample with a statistically relevant number of ions. A new CDMS instrument with an electrostatic ion trap is proposed that in combination with a new data analysis method, has the potential to increase the speed of analysis of CDMS by up to 25x. This will be done using a unique differential detection method that reduces noise and increases signal while not adversely affecting ion trapping times. Additional gains in performance will be achieved by developing a new method of data analysis to determine the phase of individual ions to make possible absorption mode (as opposed to magnitude mode that is typically used) for the first time in CDMS. By reducing the data acquisition time required to obtain mass spectra to several seconds, new applications will become possible, including combining CDMS with in-line separation methods, rapid measurements of protein aggregation kinetics, variable temperature electrospray ionization, etc. Aerodynamic acceleration currently limits the mass range of trapped ion CDMS to a few GDa. Two new innovations, a reduced pressure electrospray ionization source and a two-stage funnel will extend these measurements to the 100s of GDa mass range (500+ nm particles), making accurate mass measurements possible for a wide range of particles that are challenging to rapidly characterize by other methods. The performance of the instrument will be rigorously tested using well characterized particle standards and developments of this technology will be guided by information learned from a variety of sample types of importance to human health. These experiments include characterizing distributions of mRNA packaging in lipid nanoparticles, antibody binding to adeno-associated viruses for prediction of adverse immune response in gene therapy, and analysis of extracellular vesicles that could lead to new methods of disease detection at early stages.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $1,497,178 )
2026	2026	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	119 CALIFORNIA HALL	BERKELEY	CA	94720	ALAMEDA	USA	Biomedical Research and Research Training	001	5	5/20/2026	COMPETING CONTINUATION	$1,497,198
2026	2023	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	119 CALIFORNIA HALL	BERKELEY	CA	94720	ALAMEDA	USA	Biomedical Research and Research Training	000	4	4/28/2026	NON-COMPETING CONTINUATION	-$20
														Subtotal = $1,497,178

Issue Date FY: 2023 ( Subtotal = $301,833 )
2023	2023	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 201	BERKELEY	CA	94710	ALAMEDA	USA	Biomedical Research and Research Training	000	4	9/20/2023	NON-COMPETING CONTINUATION	$301,833
														Subtotal = $301,833

Issue Date FY: 2022 ( Subtotal = $301,833 )
2022	2022	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 201	BERKELEY	CA	94710	ALAMEDA	USA	Biomedical Research and Research Training	000	3	8/26/2022	NON-COMPETING CONTINUATION	$301,833
														Subtotal = $301,833

Issue Date FY: 2021 ( Subtotal = $301,833 )
2021	2021	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 220	BERKELEY	CA	94710	ALAMEDA	USA	Biomedical Research and Research Training	000	2	8/22/2021	NON-COMPETING CONTINUATION	$301,833
														Subtotal = $301,833

Issue Date FY: 2020 ( Subtotal = $517,350 )
2020	2020	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 220	BERKELEY	CA	94710	ALAMEDA	USA	Biomedical Research and Research Training	000	1	9/22/2020	NEW	$517,350
														Subtotal = $517,350

Grand Total All Awards = $2,920,027

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Multiplexed Charge Detection Mass Spectrometer for Extended Mass and Collisional Cross Section Measurements

Award Number: R01GM139338

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/22/2020

PERIOD OF PERFORMANCE END DATE: 05/31/2030

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