Capturing Isomeric Heterogeneity and Structural Dynamics Using Transformative Ion Manipulation Platforms
openNIGMS - National Institute of General Medical Sciences
Project Summary/Abstract
Chemical separations are foundational to modern chemistry, yet traditional liquid
chromatography-mass spectrometry workflows often fail to detect many isomeric and
conformational features of biomolecules critical to metabolism, disease, and drug efficacy. To
address these limitations, the Clowers Research Group (CRG) at Washington State University is
advancing ion mobility spectrometry and mass spectrometry techniques, leveraging gas-phase
ion chemistry and high-resolution separations enabled by Structures for Lossless Ion
Manipulations (SLIM). SLIM technology’s extended cyclic separations and controlled gas
environments allow for the resolution of isomers and intermediates that conventional methods
frequently miss.
To quantitatively capture isomeric heterogeneity in complex biological systems, the CRG is
implementing tailored multiplexed ion strategies such as Phased Ion Mobility Spectrometry. This
technique aligns SLIM separations with ultra-performance liquid chromatography timescales,
reducing spectral ambiguity and improving the resolution of co-eluting isomers in diverse ‘omics
applications. Complementing these strategies, the group is integrating gas-phase labeling
techniques, including hydrogen-deuterium exchange (gHDX) and ozone-induced dissociation.
These methods provide dynamic insights into molecular interactions by capturing solvent-
accessible regions and chemically selective modifications, enhancing the characterization of
isomeric and conformational states. The integration of tandem collision-induced unfolding with
SLIM and gHDX adds another layer of analytical depth, enabling the isolation and detailed
examination of intermediate protein structures. This approach reveals conformational transitions
and solvent-accessible regions during unfolding, helping to quantify molecular stability and refine
structural models of biopolymers.
By combining SLIM-based separations, multiplexing strategies, and gas-phase labeling
workflows, the CRG’s research program is redefining bioanalytical approaches. These
innovations aim to enhance the detection of isomeric heterogeneity, reduce analytical errors, and
provide new insights into metabolomics, lipidomics, and structural biology in support of public
health outcomes.
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Up to $406K
health research