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Multiscale Modeling of Enzymatic Reactions and Firefly Bioluminescence

Award Number: R01GM135392
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: 09/20/2019
PERIOD OF PERFORMANCE END DATE: 08/31/2024

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Multiscale Modeling of Enzymatic Reactions and Firefly Bioluminescence - Abstract Enzyme functionality is a critical component of all life systems. Whereas advances in experimental methodology have enabled a better understanding of factors that control enzyme function, critical components of the reaction space such as highly unstable intermediates and transition states are best accessed for evaluation through computational simulations. Similarly, computational methodology continues to provide a key resource for probing excited-state processes such as bioluminescence. Combined ab initio quantum mechanical molecular mechanical (ai-QM/MM) simulations are, in principle, the preferred choice in the modeling of both processes. But ai-QM/MM modeling of enzymatic reactions is now severely limited by its computational cost, where a direct ai-QM/MM free energy simulation of an enzymatic reaction can take 500,000 or more CPU hours. Meanwhile, ai-QM/MM modeling of firefly bioluminescence is also hindered by the computational accuracy, where it has yet to produce quantitatively correct predictions for the bioluminescence spectral shift with site-directed mutagenesis. The goal of this proposal is to accelerate ai-QM/MM simulations of enzymatic reaction free energy and to improve the quality of ai-QM/MM-simulated bioluminescence spectra, so that ai-QM/MM simulations can be routinely performed by experimental groups. This will be achieved via a) using a lower-level (semi-empirical QM/MM) Hamiltonian for sampling; b) an enhancement to the similarity between the two Hamiltonians by calibrating the low-level Hamiltonian using the reaction pathway force matching approach, in conjunction with several other methods. The expected outcomes of this collaborative effort include: a) advanced methodologies for accelerated reaction free energy simulations and accurate bioluminescence spectra predictions, which will be released through multiple software platforms; b) a fundamental understanding of reactions such as Kemp elimination and polymerase-eta catalyzed DNA replication; c) a deeper insight into the role of macromolecular environment in the modulation of enzyme catalytic activities or bioluminescence wavelengths, which can further enhance our capability of designing new enzymes and bioluminescence probes.


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: 2025 ( Subtotal = $0 )
2025	2022	UNIVERSITY OF OKLAHOMA	660 PARRINGTON OVAL RM 301	NORMAN	OK	73019	CLEVELAND	USA	Biomedical Research and Research Training	000	4	4/7/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $254,459 )
2022	2022	UNIVERSITY OF OKLAHOMA	1000 ASP AVE RM 105	NORMAN	OK	73019	CLEVELAND	USA	Biomedical Research and Research Training	000	4	9/2/2022	NON-COMPETING CONTINUATION	$254,459
														Subtotal = $254,459

Issue Date FY: 2021 ( Subtotal = $254,846 )
2021	2021	UNIVERSITY OF OKLAHOMA	1000 ASP AVE RM 105	NORMAN	OK	73019	CLEVELAND	USA	Biomedical Research and Research Training	000	3	8/27/2021	NON-COMPETING CONTINUATION	$254,846
														Subtotal = $254,846

Issue Date FY: 2020 ( Subtotal = $255,238 )
2020	2020	UNIVERSITY OF OKLAHOMA	1000 ASP AVE RM 105	NORMAN	OK	73019	CLEVELAND	USA	Biomedical Research and Research Training	000	2	8/10/2020	NON-COMPETING CONTINUATION	$255,238
														Subtotal = $255,238

Issue Date FY: 2019 ( Subtotal = $269,849 )
2019	2019	UNIVERSITY OF OKLAHOMA	1000 ASP AVE RM 105	NORMAN	OK	73019	CLEVELAND	USA	Biomedical Research and Research Training	000	1	9/19/2019	NEW	$269,849
														Subtotal = $269,849

Grand Total All Awards = $1,034,392

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Multiscale Modeling of Enzymatic Reactions and Firefly Bioluminescence

Award Number: R01GM135392

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: 09/20/2019

PERIOD OF PERFORMANCE END DATE: 08/31/2024

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