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Open data-driven infrastructure for building biomolecular force fields for predictive biophysics and drug design

Award Number: R01GM132386
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: 03/01/2020
PERIOD OF PERFORMANCE END DATE: 12/31/2025

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Open data-driven infrastructure for building biomolecular force fields for predictive biophysics and drug design - PROJECT SUMMARY/ABSTRACT The study of biomolecular interactions and design of new therapeutics requires accurate physical models of the atomistic interactions between small molecules and biological macromolecules. Over the least few decades, molecular mechanics force ﬁelds have demonstrated the potential that physical models hold for quantitative biophysical modeling and predictive molecular design. However, a signiﬁcant technology gap exists in our ability to build force ﬁelds that achieve high accuracy, can be systematically improved in a statistically robust manner, be extended to new areas of chemistry, can model post-translational and covalent modiﬁcations, are able to quantify systematic errors in predictions, and can be broadly applied across a high-performance software packages. In this project, we aim to bridge this technology gap to enable new generations of accurate quantitative biomolec- ular modeling and (bio)molecular design for chemical biology and drug discovery. In Aim 1, we will produce a modern, open infrastructure to enable practitioners to rapidly and conveniently construct and employ accurate and statistically robust physical force ﬁelds via automated machine learning methods. In Aim 2, we will construct open, machine-readable experimental and quantum chemical datasets that will accelerate next-generation force ﬁeld development. In Aim 3, we will develop statistically robust Bayesian inference techniques to enable the auto- mated construction of type assignment schemes that avoid overﬁtting and selection of physical functional forms statistically justﬁed by the data. This approach will also provide an estimate of the systematic error in predicted properties arising from uncertainty in parameters or functional form choices—generally the dominant source of error—to be quantiﬁed with little added expense. In Aim 4, we will integrate and apply this infrastructure to produce open, transferable, self-consistent force ﬁelds that achieve high accuracy and broad coverage for modeling small molecule interactions with biomolecules (including unnatural amino or nucleic acids and covalent modiﬁcations by organic molecules), with the ultimate goal of covering all major biomolecules. This research is signiﬁcant in that the technology developed in this project has the potential to radically transform the study of biomolecular phenomena by providing highly accurate force ﬁelds with exceptionally broad chemical coverage via fully consistent parameterization of organic (bio)molecules. In addition, we will produce new tools to automate force ﬁeld creation and tailoring to speciﬁc problem domains, quantify the systematic error in predictions, and identify new data for improving force ﬁeld accuracy. This will greatly improve our ability to study diverse biophysical processes at the molecular level, and to rationally design new small-molecule, protein, and nucleic acid therapeutics. This approach will bring statistical rigor to the ﬁeld of force ﬁeld construction and application by providing a means to make data-driven decisions, while enhancing reproducibility by enabling it to become a rigorous and reproducible science using a fully open infrastructure and datasets.


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	2023	THE REGENTS OF THE UNIVERSITY OF COLORADO	3100 MARINE ST	BOULDER	CO	80309	BOULDER	USA	Biomedical Research and Research Training	000	4	3/28/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $601,611 )
2023	2023	REGENTS OF THE UNIVERSITY OF COLORADO, THE	3100 MARINE ST STE 481 572 UCB	BOULDER	CO	80309	BOULDER	USA	Biomedical Research and Research Training	000	4	4/21/2023	NON-COMPETING CONTINUATION	$601,611
														Subtotal = $601,611

Issue Date FY: 2022 ( Subtotal = $731,709 )
2022	2022	REGENTS OF THE UNIVERSITY OF COLORADO, THE	3100 MARINE ST STE 481 572 UCB	BOULDER	CO	80309	BOULDER	USA	Biomedical Research and Research Training	002	3	7/11/2022	SUPPLEMENT FOR EXPANSION	$10,780
2022	2022	REGENTS OF THE UNIVERSITY OF COLORADO, THE	3100 MARINE ST STE 481 572 UCB	BOULDER	CO	80309	BOULDER	USA	Biomedical Research and Research Training	001	3	6/29/2022	NON-COMPETING CONTINUATION	$72,095
2022	2022	REGENTS OF THE UNIVERSITY OF COLORADO, THE	3100 MARINE ST STE 481 572 UCB	BOULDER	CO	80309	BOULDER	USA	Biomedical Research and Research Training	000	3	2/24/2022	NON-COMPETING CONTINUATION	$648,834
														Subtotal = $731,709

Issue Date FY: 2021 ( Subtotal = $786,542 )
2021	2021	REGENTS OF THE UNIVERSITY OF COLORADO, THE	3100 MARINE ST STE 481 572 UCB	BOULDER	CO	80309	BOULDER	USA	Biomedical Research and Research Training	000	2	2/18/2021	NON-COMPETING CONTINUATION	$608,856
2021	2021	REGENTS OF THE UNIVERSITY OF COLORADO, THE	3100 MARINE ST STE 481 572 UCB	BOULDER	CO	80309	BOULDER	USA	Biomedical Research and Research Training	005	2	8/30/2021	SUPPLEMENT FOR EXPANSION	$177,686
2021	2021	REGENTS OF THE UNIVERSITY OF COLORADO, THE	3100 MARINE ST STE 481 572 UCB	BOULDER	CO	80309	BOULDER	USA	Biomedical Research and Research Training	004	2	4/9/2021	NON-COMPETING CONTINUATION	$0
2021	2020	REGENTS OF THE UNIVERSITY OF COLORADO, THE	3100 MARINE ST STE 481 572 UCB	BOULDER	CO	80309	BOULDER	USA	Biomedical Research and Research Training	002	1	4/2/2021	SUPPLEMENT FOR EXPANSION	$0
2021	2020	REGENTS OF THE UNIVERSITY OF COLORADO, THE	3100 MARINE ST STE 481 572 UCB	BOULDER	CO	80309	BOULDER	USA	Biomedical Research and Research Training	003	1	4/2/2021	SUPPLEMENT FOR EXPANSION	$0
2021	2020	REGENTS OF THE UNIVERSITY OF COLORADO, THE	3100 MARINE ST STE 481 572 UCB	BOULDER	CO	80309	BOULDER	USA	Biomedical Research and Research Training	001	1	4/2/2021	NEW	$0
														Subtotal = $786,542

Issue Date FY: 2020 ( Subtotal = $996,568 )
2020	2020	REGENTS OF THE UNIVERSITY OF COLORADO, THE	3100 MARINE ST STE 481 572 UCB	BOULDER	CO	80309	BOULDER	USA	Biomedical Research and Research Training	002	1	9/1/2020	SUPPLEMENT FOR EXPANSION	$225,000
2020	2020	REGENTS OF THE UNIVERSITY OF COLORADO, THE	3100 MARINE ST STE 481 572 UCB	BOULDER	CO	80309	BOULDER	USA	Biomedical Research and Research Training	001	1	6/25/2020	SUPPLEMENT FOR EXPANSION	$96,003
2020	2020	REGENTS OF THE UNIVERSITY OF COLORADO, THE	3100 MARINE ST STE 481 572 UCB	BOULDER	CO	80309	BOULDER	USA	Biomedical Research and Research Training	000	1	2/12/2020	NEW	$675,565
														Subtotal = $996,568

Grand Total All Awards = $3,116,430

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Open data-driven infrastructure for building biomolecular force fields for predictive biophysics and drug design

Award Number: R01GM132386

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: 03/01/2020

PERIOD OF PERFORMANCE END DATE: 12/31/2025

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