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Determination of the Structure, Dynamics and Energetics of Enzyme Reactions

Award Number: R35GM163614
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: 08/10/2026
PERIOD OF PERFORMANCE END DATE: 07/31/2030

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Determination of the Structure, Dynamics and Energetics of Enzyme Reactions - A. Project Summary/Abstract “How do enzymes work?” This basic question is of central importance in biochemistry and, given the ubiquitous role of enzymes in life and disease processes, in the biomedical sciences. Answering the question entails knowledge of how each atom in the system moves and how the free energy changes as the reaction progresses to provide atomic-level detail of the structural, dynamic and energetic features over the entire reaction path. In reality, only incomplete and indirect knowledge is currently accessible, requiring the application of a combined methodology that bridges the many timescales of the reaction. The present application addresses two important challenges: (i) the development of very fast methods for the study of enzymatic transition states and (ii) studies of how and enzyme catalyzes a complex reaction. Supported by the current R01 funding, we made significant progress towards both challenges, demonstrating in a series of released publications, codes and structures that the innovative approach of coupling reaction- specific transition state force fields (TSFFs) with time-resolved crystallography (TRC) results is up to these challenges. The power of these methods was demonstrated for the case of Pseudomonas mevalonii HMG CoA reductase (pmHMGR), which was chosen because it: 1) has a complex reaction mechanism involving two hydride transfers, a thiohemiacetal breakdown and two cofactor exchange steps, 2) can be reversible run in the crystal and 3) has a wealth of experimental data for the validation of the methodology available. It is also representative of many other enzymes to which this methodology could be applied. Future work towards Important Challenge 1 will address the fact that TSFFs are reaction specific and need to be refitted for each reaction by accelerating and automating the quantum-guided molecular mechanics (Q2MM) method with two innovations: (i) FUERZA, which generates improved initial guess for force constants by projecting out cross-terms between the reparameterized and literature force field terms and (ii) a e-constrained particle swarm optimizer (PSO) to automate the minimization of the merit function in a high dimensional, multi-minima space. We will then demonstrate the generality of this approach by applying fitting TSFFs for the distinct chemical reactions catalyzed by pmHMGR. For Important Challenge 2, we will ) use the TSFFs for µsec MD simulations with the long-term goal of generating overlapping ensembles along the entire reaction pathway of pmHMGR, including the chemically most relevant portions around the transition states. Analysis of the MD trajectories using Markov State Models (MSM) and Generalized Master Equation (GME) techniques that provides the structures used in these workflows and informs the most informative time points that are validated by iteratively linking them to TRC in a physically rigorous manner. Some of the TRC data is already in hand while higher time resolution data will be generated in collaboration improved pH jump and rapid-freeze methods by extending the existing collaboration with the Stauffacher and Cohen groups. 1


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 = $1,950,803 )
2026	2026	UNIVERSITY OF NOTRE DAME DU LAC	940 GRACE HALL	NOTRE DAME	IN	46556	ST JOSEPH	USA	Biomedical Research and Research Training	000	1	8/5/2026	NEW	$1,950,803
														Subtotal = $1,950,803

Grand Total All Awards = $1,950,803

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Determination of the Structure, Dynamics and Energetics of Enzyme Reactions

Award Number: R35GM163614

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: 08/10/2026

PERIOD OF PERFORMANCE END DATE: 07/31/2030

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