Tuesday, April 1, 2025 4/1/2025

Calculating Ensembles of Discrete Dynamic Complexes and Condensed States of Intrinsically Disordered Proteins

Award Number: R01GM127627
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Calculating Ensembles of Discrete Dynamic Complexes and Condensed States of Intrinsically Disordered Proteins - The traditional structure-function paradigm has provided significant insights for well-folded proteins in which structures can be easily and rapidly revealed by X-ray crystallography beamlines and NMR. However approximately one third of the human proteome are comprised of intrinsically disordered proteins and regions that do not adopt a dominant well-folded structure, and therefore remain “unseen” by traditional structural biology methods. Current experimental and computational approaches to structural descriptions of disordered proteins, while often valuable, still lack predictive power, particularly for dynamic complexes of IDPs, as well as lack of insight into the relationships between IDP structural ensembles and function. We made significant progress in the last grant cycle in the following four directions: (1) Generating and quantifying the utility of experimental data types for IDP monomer ensembles; (2) Applying atomistic and coarse-grained physical models and machine learned sampling methods for generating monomer ensembles; (3) Advancing new Bayesian models for IDP monomer ensemble selection; (4) development of highly novel machine learning (ML) methodology for ensemble generation and selection; (5) Creating software and monomer ensemble data and placing them in the hands of practitioners. Many of these results serve as preliminary studies for this renewal and are described in more detail in proposed research. But to fully address the biological activity of IDPs we propose to adapt these computational methods further and develop new integrative biology tools that will be more selective for dynamic associations of IDPs within both discrete dynamic complexes and biological condensates and for post-translational modifications (PTMs) that create relevant IDP functional states. Building on strong preliminary data from our experimental collaborators, we will record NMR, SAXS and single molecule fluorescence data on phosphorylated and non-phosphorylated 4E-binding protein 2 (np-4E-BP2, 5p-4E-BP2) and its dynamic complex with the eukaryotic translation initiation factor (eIF4E); tropoelastin and mixed and condensed-phase elastin fragments; and mixed and condensed-phase CAPRIN1 C-terminal IDR, including novel NMR experiments that probe electrostatic potentials (ESPs), 3-color smFRET, and fluorescence correlation spectroscopy (FCS). These studies will illuminate mechanisms of translational regulation and elasticity, and provide insights into pathological states, including autism spectrum disorder and cardiovascular disease.


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 = $246,694 )
2025	2025	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 201	BERKELEY	CA	94710	ALAMEDA	USA	Biomedical Research and Research Training	000	7	3/3/2025	NON-COMPETING CONTINUATION	$246,694
														Subtotal = $246,694

Issue Date FY: 2024 ( Subtotal = $252,324 )
2024	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 201	BERKELEY	CA	94710	ALAMEDA	USA	Biomedical Research and Research Training	002	6	2/21/2024	NON-COMPETING CONTINUATION	$227,091
2024	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 201	BERKELEY	CA	94710	ALAMEDA	USA	Biomedical Research and Research Training	003	6	6/17/2024	NON-COMPETING CONTINUATION	$25,233
2024	2023	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 201	BERKELEY	CA	94710	ALAMEDA	USA	Biomedical Research and Research Training	001	5	1/25/2024	COMPETING CONTINUATION	$9
2024	2021	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 201	BERKELEY	CA	94710	ALAMEDA	USA	Biomedical Research and Research Training	000	4	1/25/2024	NON-COMPETING CONTINUATION	-$9
														Subtotal = $252,324

Issue Date FY: 2023 ( Subtotal = $325,860 )
2023	2023	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 201	BERKELEY	CA	94710	ALAMEDA	USA	Biomedical Research and Research Training	000	5	2/16/2023	COMPETING CONTINUATION	$325,860
														Subtotal = $325,860

Issue Date FY: 2021 ( Subtotal = $253,341 )
2021	2021	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 220	BERKELEY	CA	94710	ALAMEDA	USA	Biomedical Research and Research Training	000	4	2/12/2021	NON-COMPETING CONTINUATION	$253,341
														Subtotal = $253,341

Issue Date FY: 2020 ( Subtotal = $251,770 )
2020	2020	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 220	BERKELEY	CA	94710	ALAMEDA	USA	Biomedical Research and Research Training	000	3	2/26/2020	NON-COMPETING CONTINUATION	$251,770
														Subtotal = $251,770

Issue Date FY: 2019 ( Subtotal = $251,094 )
2019	2019	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 220	BERKELEY	CA	94710	ALAMEDA	USA	Biomedical Research and Research Training	000	2	3/7/2019	NON-COMPETING CONTINUATION	$251,094
														Subtotal = $251,094

Issue Date FY: 2018 ( Subtotal = $264,790 )
2018	2018	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	2150 SHATTUCK AVE RM 313	BERKELEY	CA	94704	ALAMEDA	USA	Biomedical Research and Research Training	000	1	4/25/2018	NEW	$264,790
														Subtotal = $264,790

Grand Total All Awards = $1,845,873

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Calculating Ensembles of Discrete Dynamic Complexes and Condensed States of Intrinsically Disordered Proteins

Award Number: R01GM127627

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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