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Structure and Relations of Protein and Nucleic Acids

Award Number: R01GM015792
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: 01/01/1978
PERIOD OF PERFORMANCE END DATE: 12/31/2025

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Structure and Relations of Protein and Nucleic Acids - Project Summary – Abstract In this renewal application we describe recent progress in our ongoing studies of DNA-protein interactions, which have focused largely during the last grant cycle on understanding the molecular mechanisms involved in the assembly, function and control of the macromolecular complexes that direct DNA replication in bacteriophage T4, and outline our plans for the next five years. For many years Peter von Hippel served as the sole PI of this grant, but now this program is a tightly knit joint collaboration between the research groups of Professors Andrew Marcus and Peter von Hippel at the University of Oregon, who serve jointly as co-PIs of this research project. In earlier work supported by this grant, the von Hippel lab focused on solution studies of the replication complex of bacteriophage T4 and the transcription complex of E. coli. We note that these systems involve essentially the same molecular mechanisms for `driving' and regulating these central life processes as do those of `higher organisms,' including humans. These studies thus provide good model systems to examine how human DNA replication proceeds at the functional level, and can help provide insights into what might go wrong in various genetic diseases, which are often caused by minor quantitative changes in the properties of the `macromolecular machines' of genome expression. During the previous reporting period we completed a number of studies on the above mechanistic questions, using reconstituted DNA replication assemblies that carry out their functions in vitro with essentially the same rates, fidelities and processivities as do the in vivo versions of these complexes. We proceeded by placing fluorescent base analogue probes, or cyanine dyes, at defined positions within the DNA frameworks of the reconstituted complexes, and then used fluorescence and circular dichroism spectroscopy to monitor biologically relevant conformational changes at and near the probe labeling sites. In this way, we obtained significant information about replication mechanisms under steady-state or equilibrium conditions, and then carried forward this work by demonstrating that these same optical probe-labeling strategies can be used in more complex experiments to permit two-dimensional fluorescence spectroscopy (2DFS), single-molecule Förster Resonance Energy Transfer (smFRET) and Fluorescence-detected Linear Dichroism (smFLD), which provide structural interpretations and follow the kinetics of reactions within these complexes in `real time' with µsec to msec resolution. As described in the present proposal, these approaches now permit us to obtain structural and dynamic information about local conformational changes that occur at defined and biologically-relevant base analogue and DNA backbone probe sites, as well as to determine free energy surfaces (and define transition states) of individual rate-limiting molecular steps within reconstituted models of relatively complete DNA replication complexes. Using these approaches, we are beginning to reveal mechanisms of regulatory control systems that have previously been inaccessible to direct experimental measurement.


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 = $358,437 )
2025	2025	UNIVERSITY OF OREGON	1776 E 13TH AVE	EUGENE	OR	97403	LANE	USA	Biomedical Research and Research Training	000	58	12/10/2024	NON-COMPETING CONTINUATION	$358,437
														Subtotal = $358,437

Issue Date FY: 2024 ( Subtotal = $538,021 )
2024	2024	UNIVERSITY OF OREGON	1585 E 13TH AVE	EUGENE	OR	97403	LANE	USA	Biomedical Research and Research Training	000	57	12/18/2023	NON-COMPETING CONTINUATION	$358,437
2024	2024	UNIVERSITY OF OREGON	1776 E 13TH AVE	EUGENE	OR	97403	LANE	USA	Biomedical Research and Research Training	002	57	8/14/2024	SUPPLEMENT FOR EXPANSION	$139,759
2024	2024	UNIVERSITY OF OREGON	1776 E 13TH AVE	EUGENE	OR	97403	LANE	USA	Biomedical Research and Research Training	001	57	6/17/2024	NON-COMPETING CONTINUATION	$39,825
														Subtotal = $538,021

Issue Date FY: 2023 ( Subtotal = $530,022 )
2023	2023	UNIVERSITY OF OREGON	1585 E 13TH AVE	EUGENE	OR	97403	LANE	USA	Biomedical Research and Research Training	008	56	8/3/2023	SUPPLEMENT FOR EXPANSION	$131,760
2023	2023	UNIVERSITY OF OREGON	1585 E 13TH AVE	EUGENE	OR	97403	LANE	USA	Biomedical Research and Research Training	006	56	2/15/2023	NON-COMPETING CONTINUATION	$39,825
2023	2023	UNIVERSITY OF OREGON	1585 E 13TH AVE	EUGENE	OR	97403	LANE	USA	Biomedical Research and Research Training	004	56	1/9/2023	NON-COMPETING CONTINUATION	$358,437
2023	2022	UNIVERSITY OF OREGON	1585 E 13TH AVE	EUGENE	OR	97403	LANE	USA	Biomedical Research and Research Training	001	55	11/10/2022	COMPETING CONTINUATION	$8,129
2023	2022	UNIVERSITY OF OREGON	1585 E 13TH AVE	EUGENE	OR	97403	LANE	USA	Biomedical Research and Research Training	007	55	2/16/2023	COMPETING CONTINUATION	$8,072
2023	2022	UNIVERSITY OF OREGON	1585 E 13TH AVE	EUGENE	OR	97403	LANE	USA	Biomedical Research and Research Training	003	55	11/29/2022	COMPETING CONTINUATION	-$8,129
2023	2021	UNIVERSITY OF OREGON	1585 E 13TH AVE	EUGENE	OR	97403	LANE	USA	Biomedical Research and Research Training	005	54	2/2/2023	NON-COMPETING CONTINUATION	-$8,072
2023	2021	UNIVERSITY OF OREGON	1585 E 13TH AVE	EUGENE	OR	97403	LANE	USA	Biomedical Research and Research Training	002	54	11/29/2022	NON-COMPETING CONTINUATION	$8,129
2023	2021	UNIVERSITY OF OREGON	1585 E 13TH AVE	EUGENE	OR	97403	LANE	USA	Biomedical Research and Research Training	000	54	11/10/2022	NON-COMPETING CONTINUATION	-$8,129
														Subtotal = $530,022

Issue Date FY: 2022 ( Subtotal = $398,262 )
2022	2022	UNIVERSITY OF OREGON	1585 E 13TH AVE	EUGENE	OR	97403	LANE	USA	Biomedical Research and Research Training	000	55	12/20/2021	COMPETING CONTINUATION	$398,262
														Subtotal = $398,262

Issue Date FY: 2021 ( Subtotal = $368,750 )
2021	2021	UNIVERSITY OF OREGON	1585 E 13TH AVE	EUGENE	OR	97403	LANE	USA	Biomedical Research and Research Training	001	54	3/1/2021	NON-COMPETING CONTINUATION	$36,878
2021	2021	UNIVERSITY OF OREGON	1585 E 13TH AVE	EUGENE	OR	97403	LANE	USA	Biomedical Research and Research Training	000	54	12/21/2020	NON-COMPETING CONTINUATION	$331,872
														Subtotal = $368,750

Issue Date FY: 2020 ( Subtotal = $368,750 )
2020	2020	UNIVERSITY OF OREGON	1585 E 13TH AVE	EUGENE	OR	97403	LANE	USA	Biomedical Research and Research Training	000	53	2/17/2020	NON-COMPETING CONTINUATION	$368,750
														Subtotal = $368,750

Issue Date FY: 2019 ( Subtotal = $499,597 )
2019	2019	UNIVERSITY OF OREGON	1585 E 13TH AVE	EUGENE	OR	97403	LANE	USA	Biomedical Research and Research Training	003	52	9/25/2019	SUPPLEMENT FOR EXPANSION	$130,847
2019	2019	UNIVERSITY OF OREGON	1585 E 13TH AVE	EUGENE	OR	97403	LANE	USA	Biomedical Research and Research Training	000	52	12/25/2018	NON-COMPETING CONTINUATION	$368,750
2019	2018	UNIVERSITY OF OREGON	1585 E 13TH AVE	EUGENE	OR	97403	LANE	USA	Biomedical Research and Research Training	001	51	4/22/2019	COMPETING CONTINUATION	$58
2019	2017	UNIVERSITY OF OREGON	1585 E 13TH AVE	EUGENE	OR	97403	LANE	USA	Biomedical Research and Research Training	002	50	4/22/2019	SUPPLEMENT FOR EXPANSION	-$58
														Subtotal = $499,597

Issue Date FY: 2018 ( Subtotal = $602,750 )
2018	2018	UNIVERSITY OF OREGON	1585 E 13TH AVE	EUGENE	OR	97403	LANE	USA	Biomedical Research and Research Training	002	51	12/20/2017	COMPETING CONTINUATION	$418,750
2018	2018	UNIVERSITY OF OREGON	1585 E 13TH AVE	EUGENE	OR	97403	LANE	USA	Biomedical Research and Research Training	005	51	9/17/2018	SUPPLEMENT FOR EXPANSION	$184,000
2018	2018	UNIVERSITY OF OREGON	1585 E 13TH AVE	EUGENE	OR	97403	LANE	USA	Biomedical Research and Research Training	003	51	8/2/2018	COMPETING CONTINUATION	$32,556
2018	2017	UNIVERSITY OF OREGON	1585 E 13TH AVE	EUGENE	OR	97403	LANE	USA	Biomedical Research and Research Training	004	50	8/2/2018	SUPPLEMENT FOR EXPANSION	-$32,556
2018	2017	UNIVERSITY OF OREGON	1585 E 13TH AVE	EUGENE	OR	97403	LANE	USA	Biomedical Research and Research Training	001	50	12/18/2017	SUPPLEMENT FOR EXPANSION	$0
2018	2016	UNIVERSITY OF OREGON	1585 E 13TH AVE	EUGENE	OR	97403	LANE	USA	Biomedical Research and Research Training	000	50	12/15/2017	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $602,750

Issue Date FY: 2017 ( Subtotal = $119,751 )
2017	2017	UNIVERSITY OF OREGON	1585 E 13TH AVE	EUGENE	OR	97403	LANE	USA	Biomedical Research and Research Training	000	50	8/1/2017	SUPPLEMENT FOR EXPANSION	$119,751
2017	2016	UNIVERSITY OF OREGON	1585 E 13TH AVE	EUGENE	OR	97403	LANE	USA	Biomedical Research and Research Training	001	50	8/2/2017	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $119,751

Issue Date FY: 2016 ( Subtotal = $353,162 )
2016	2016	UNIVERSITY OF OREGON	POST OFFICE BOX 3237	EUGENE	OR	97403	LANE	USA	Biomedical Research and Research Training	000	50	3/14/2016	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$353,162
														Subtotal = $353,162

Issue Date FY: 2015 ( Subtotal = $353,162 )
2015	2015	UNIVERSITY OF OREGON	5219 UNIVERSITY OF OREGON	EUGENE	OR	97403	LANE	USA	Biomedical Research and Research Training	000	49	3/19/2015	NON-COMPETING CONTINUATION	$353,162
														Subtotal = $353,162

Issue Date FY: 2014 ( Subtotal = $381,098 )
2014	2014	UNIVERSITY OF OREGON	5219 UNIVERSITY OF OREGON	EUGENE	OR	97403	LANE	USA	Biomedical Research and Research Training	000	48	3/25/2014	COMPETING CONTINUATION	$381,098
														Subtotal = $381,098

Issue Date FY: 2013 ( Subtotal = $362,866 )
2013	2013	UNIVERSITY OF OREGON	5219 UNIVERSITY OF OREGON	EUGENE	OR	97403	LANE	USA	Biomedical Research and Research Training	000	47	3/25/2013	NON-COMPETING CONTINUATION	$338,424
2013	2013	UNIVERSITY OF OREGON	5219 UNIVERSITY OF OREGON	EUGENE	OR	97403	LANE	USA	Biomedical Research and Research Training	001	47	6/17/2013	NON-COMPETING CONTINUATION	$24,442
														Subtotal = $362,866

Issue Date FY: 2012 ( Subtotal = $374,330 )
2012	2012	UNIVERSITY OF OREGON	5219 UNIVERSITY OF OREGON	EUGENE	OR	97403	LANE	USA	Biomedical Research and Research Training	000	46	4/6/2012	NON-COMPETING CONTINUATION	$374,330
														Subtotal = $374,330

Issue Date FY: 2011 ( Subtotal = $426,867 ) (Continued on the next page)
Grand Total All Awards = $10,780,783

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Structure and Relations of Protein and Nucleic Acids

Award Number: R01GM015792

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: 01/01/1978

PERIOD OF PERFORMANCE END DATE: 12/31/2025

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