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Robust atomic-level enzymatic activity study by time-resolved crystallography and computational enzymology

Award Number: R00GM147598
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: 08/15/2022
PERIOD OF PERFORMANCE END DATE: 12/31/2028

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Robust atomic-level enzymatic activity study by time-resolved crystallography and computational enzymology - The inability to visualize enzymes in action at atomic resolution constitutes a major technological barrier in biology, stalling mechanistic understanding and hindering the rational design of therapeutics for numerous human diseases. This project directly addresses this critical barrier by developing and generalizing a powerful, integrated methodology combining time-resolved X-ray crystallography with quantum mechanics/molecular mechanics {TRX-QM/MM) simulations. The power of this approach has been demonstrated through the fundamental reversal of the accepted paradigm for ATP hydrolysis in Hsp70 chaperones, a discovery built on an unprecedented dataset of time-resolved structures. The overarching goal of the independent R00 phase is to leverage this breakthrough to establish a broadly applicable platform for deciphering the mechanisms of challenging enzymatic systems. The central hypothesis is that mechanistically distinct enzymes require different catalytic strategies that can only be resolved by our integrated approach. The specific aims are: 1) To provide an atomic-level motion picture of Hsp70 catalysis by capturing key intermediates to define the energy landscape of its novel dissociative mechanism and the essential proton relay network. 2) To elucidate the chemomechanical gating of actin's contrasting associative ATPase mechanism, testing the general applicability of our platform on a fast, allosterically-regulated enzyme. 3) To engineer and disseminate a multi-scale platform for time-resolved enzymology by developing a next-generation mix-and-quench apparatus, integrating time-resolved MicroED to visualize proton dynamics, and implementing a novel QM/MM refinement protocol for modeling reactive intermediates. Successful completion of this project will deliver a transformative, validated toolkit for the scientific community, breaking a long-standing technological bottleneck and enabling the mechanistic investigation of a vast range of enzymes essential to human health and disease. This will provide the fundamental knowledge required to accelerate the development of next-generation, mechanism-based therapeutics.


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 = $248,432 )
2026	2026	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Biomedical Research and Research Training	000	3	1/28/2026	EXTENSION WITH OR WITHOUT FUNDS	$248,432
														Subtotal = $248,432

Grand Total All Awards = $248,432

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Robust atomic-level enzymatic activity study by time-resolved crystallography and computational enzymology

Award Number: R00GM147598

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: 08/15/2022

PERIOD OF PERFORMANCE END DATE: 12/31/2028

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