# Advancing High-Resolution Charge Detection-Mass Spectrometry

> **NIH NIH R01** · TRUSTEES OF INDIANA UNIVERSITY · 2024 · $265,939

## Abstract

Project Summary
 Charge detection mass spectrometry (CD-MS) is an emerging technology that allows accurate mass
distributions to be measured for heterogeneous and high mass samples. It is a single ion approach where the
mass to charge ratio (m/z) and charge are measured simultaneously for each ion, and then multiplied to give the
ion’s mass. Measurements are performed for thousands of ions, which are then binned into a mass distribution.
The m/z ratio and charge are measured using a detection cylinder embedded in an electrostatic linear ion trap
(ELIT). Trapped ions oscillate back and forth through the detection cylinder and the signal from the oscillating
ions is detected by a charge sensitive amplifier. The oscillation frequency gives the m/z ratio, and the charge is
obtained from the signal amplitude. CD-MS is early enough in its development cycle that substantial technical
improvements are still occurring. In this project we address the two main limitations of CD-MS: 1) its moderate
resolving power, and 2) the relatively long time needed to measure a spectrum. The mass resolving power is
limited by the precision of the m/z determination. The best m/z resolving power reported to date is 700. Using
computer simulations, we have designed ELITs with resolving powers over 300,000. However, to perform at this
level, the ELITs need to be perfectly aligned. Computer simulations indicate we can overcome the alignment
problem by segmenting some of the ELIT electrodes and applying slightly different voltages to the segments to
recover the high resolution. Our second goal is to substantially reduce the time needed to measure a spectrum.
To achieve this goal, we will a) reduce the trapping time needed to resolve charge states, and b) reduce ion-ion
interactions so that more ions can be trapped and measured at the same time. The trapping time required for
charge state resolution can be reduced by lowering electrical noise, which will be achieved by implementing a
novel design for the charge sensitive amplifier. Ion-ion interactions will be reduced by optimizing ELIT designs
so that ions are trapped in trajectories that do not interact. Combining these advances, we expect to perform
high-resolution CD-MS measurements at 500-1000 ions/s. The advances described above will be transformative
for CD-MS and are expected to have a broad impact. We will explore three applications. 1) high resolution CD-
MS analysis of the adeno-associated virus (AAV) gene therapy vectors will reveal subpopulations with different
combinations of capsid proteins. The subpopulation relative abundances, and any correlations with post
translational modifications, may help understand lot-to-lot variability in AAV preparations. 2)
Heteroaryldihydropyrimidines (HAPs) lead to aberrant assembly of hepatitis B virus (HBV) capsids, and they are
being investigated as potential HBV antivirals. High resolution CD-MS measurements will be performed to
monitor HAP binding to HBV capsids and assembly...

## Key facts

- **NIH application ID:** 10944800
- **Project number:** 1R01GM155650-01
- **Recipient organization:** TRUSTEES OF INDIANA UNIVERSITY
- **Principal Investigator:** MARTIN F JARROLD
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $265,939
- **Award type:** 1
- **Project period:** 2024-09-24 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10944800

## Citation

> US National Institutes of Health, RePORTER application 10944800, Advancing High-Resolution Charge Detection-Mass Spectrometry (1R01GM155650-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10944800. Licensed CC0.

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