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Developing an integrated system for detailing the conformational flexibility, heterogeneity, and dynamics of functional oligonucleotides

Award Number: R01GM153899
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: 07/01/2024
PERIOD OF PERFORMANCE END DATE: 04/30/2028

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Developing an integrated system for detailing the conformational flexibility, heterogeneity, and dynamics of functional oligonucleotides - Abstract/Summary Despite the nearly 4 decades of technology development for biomolecular structure analysis since the discovery of the ribozyme, researchers still grapple with an inability to characterize important intermediates and other aspects of functional nucleic acid structure. Although powerful approaches such as X-ray crystallography, NMR, and Cryo-EM can provide atomic-level detail, they are essentially blind to structural transformations, co-existing solution structures and conformational flexibility. Time-resolved NMR provides useful information about large conformation changes on long timescales; however, it is not able to detail the conformational ensemble along a folding pathway. Mass spectrometry (MS) including MS coupled with ion mobility spectrometry (IMS) are promising tools to provide additional structural detail but suffer from two disadvantages for studying functional nucleic acids. The first is a relatively low signal intensity associated with the analysis of oligonucleotides in negative ion mode. This potentially renders many important structures (e.g., low population) essentially invisible to the analysis. The second is that the ions can undergo rapid structural transformation such as compaction in the gas phase making the extraction of solution-relevant details very difficult. Overall, MS analysis requires dramatically increased sensitivity and better means to extract solution structure information to characterize important intermediates and conformational flexibility in structure establishment. Here we propose the development of a paradigm-breaking, front-end technology platform for enhanced compound ionization and improved structure resolution. The technology is built upon the new ionization technique capillary Vibrating Sharp-edge Spray Ionization (cVSSI), which is shown to provide 10-to-100-fold ion signal enhancements over state-of-the-art ESI sources in negative ion mode. This work will extend that advantage by another order of magnitude to break through the sensitivity issues associated with the characterization of functional nucleic acids. Additionally, the work will produce an integrated platform that utilizes new, rapid mixing strategies for performing hydrogen-deuterium exchange labeling kinetics as well as oligonucleotide folding kinetics. The microfluidics device will couple seamlessly with cVSSI to accomplish high sensitivity ionization as well as to permit pulsed (in-droplet and on-line) and continuous (on-line) HDX labeling. With the device it will immediately be possible to resolve co-existing structures, structural transformations, and conformer flexibility based on differences in HDX reactivity. A novel HDX kinetics modeling methodology will also be developed to allow for structure elucidation from even the shortest timescale measurements. The new technology platform will be validated with gold standard functional nucleic acids including 10-23 DNAzyme, Hairpin Ribozyme, and Group II Intron systems. The complete mapping of conformational heterogeneity and flexibilities and folding processes of these systems will open the floodgates for further work on therapeutically-important functional nucleic acids.


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 = $0 )
2026	2025	WEST VIRGINIA UNIVERSITY RESEARCH CORPORATION	886 CHESTNUT RIDGE ROAD	MORGANTOWN	WV	26505	MONONGALIA	USA	Biomedical Research and Research Training	000	2	2/10/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $486,400 )
2025	2025	WEST VIRGINIA UNIVERSITY RESEARCH CORPORATION	886 CHESTNUT RIDGE ROAD	MORGANTOWN	WV	26505	MONONGALIA	USA	Biomedical Research and Research Training	000	2	4/17/2025	NON-COMPETING CONTINUATION	$486,400
														Subtotal = $486,400

Issue Date FY: 2024 ( Subtotal = $526,400 )
2024	2024	WEST VIRGINIA UNIVERSITY RESEARCH CORPORATION	886 CHESTNUT RIDGE ROAD	MORGANTOWN	WV	26505	MONONGALIA	USA	Biomedical Research and Research Training	000	1	6/28/2024	NEW	$526,400
														Subtotal = $526,400

Grand Total All Awards = $1,012,800

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Developing an integrated system for detailing the conformational flexibility, heterogeneity, and dynamics of functional oligonucleotides

Award Number: R01GM153899

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: 07/01/2024

PERIOD OF PERFORMANCE END DATE: 04/30/2028

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