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Thermodynamics and kinetics of DNA-ligand binding probed by DNA overstretching

Award Number: SC3GM083779
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: 05/01/2008
PERIOD OF PERFORMANCE END DATE: 07/31/2017

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Thermodynamics and kinetics of DNA-ligand binding probed by DNA overstretching - DESCRIPTION (provided by applicant): Structural transitions of DNA and docking of DNA-binding ligands on DNA are fundamental processes in molecular biology. Understanding and controlling these processes are essential to the rational design of novel drugs against cancer and infectious diseases such as HIV. Single-molecule force measurements using optical and magnetic tweezers and atomic force microscopy have dramatically expanded our knowledge of nucleic acids and proteins. Specifically, stretching single DNA molecules by an optical tweezers instrument can induce the unwinding of the two strands of the DNA duplex. The induced structural and thermodynamic changes in the DNA double helix upon stretching alter interactions with DNA-binding ligands in a controllable and measurable way. Therefore single-molecule force measurements of DNA and DNA-ligand interactions provide an unprecedented opportunity for quantitative study of a wide range of physiologically important phenomena associated with DNA helix-destabilization and DNA-ligand binding. In spite of the progress made in single-molecule force experiments, a poor understanding of the structural and thermodynamic response of biomolecules to mechanical stress has limited the insight that such experiments have provided into helix destabilization and DNA-ligand binding. A notorious difficulty for modeling force-induced melting is the vast range of length and time scales spanned by the process, and by the difficulty in computing the accompanying change in entropy. To better understand the fundamental biophysics involved in crossing length and times scales from the atomistic to the macromolecular model, we develop a novel multiscale model for DNA stretching and small ligand binding to stretched DNA. This system is well characterized experimentally and sufficiently simple to facilitate chemically accurate biophysical modeling in terms of all-atom molecular dynamics (MD) simulations and coarse-grained models such as the Poland-Scheraga model. Moreover, DNA stretching in the presence of DNA binding ligands yields information about DNA ligand binding under realistic, biologically relevant conditions that cannot be obtained by other methods. In this project we study the binding of Actinomycin D (ActD), an anticancer antibiotic drug that targets DNA replication and transcription, by a multipronged approach. On the atomistic scale, chemically accurate MD simulations will be used to study the binding mechanism and dynamics of ActD to short DNA oligomers; for long DNA as used in stretching experiments, our multiscale model will be used to compute equilibrium force-extension relations that can be directly validated with experimental data. The project will both enhance our knowledge of multiscale phenomena in fundamental biophysics and provide new insight into the anticancer function of ActD.


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: 2019 ( Subtotal = -$13,085 )
2019	2016	UNIVERSITY OF TEXAS RIO GRANDE VALLEY, THE	2102 TREASURE HILLS BLVD STE 3.100	HARLINGEN	TX	78550	CAMERON	USA	Biomedical Research and Research Training	000	8	1/7/2019	NON-COMPETING CONTINUATION	-$13,085
														Subtotal = -$13,085

Issue Date FY: 2017 ( Subtotal = $18,636 )
2017	2016	UNIVERSITY OF TEXAS RIO GRANDE VALLEY (UTRGV), THE	1201 W UNIVERSITY DR	EDINBURG	TX	78539	HIDALGO	USA	Biomedical Research and Research Training	001	8	1/19/2017	NON-COMPETING CONTINUATION	$10,225
2017	2015	UNIVERSITY OF TEXAS RIO GRANDE VALLEY (UTRGV), THE	1201 W UNIVERSITY DR	EDINBURG	TX	78539	HIDALGO	USA	Biomedical Research and Research Training	000	7	1/18/2017	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$8,411
														Subtotal = $18,636

Issue Date FY: 2016 ( Subtotal = $98,750 )
2016	2016	UNIVERSITY OF TEXAS RIO GRANDE VALLEY (UTRGV)	1201 W. UNIVERSITY DR	EDINBURG	TX	78539	HIDALGO	USA	Biomedical Research and Research Training	002	8	8/2/2016	NON-COMPETING CONTINUATION	$98,750
2016	2015	UNIVERSITY OF TEXAS AT BROWNSVILLE	80 FORT BROWN	BROWNSVILLE	TX	78520	CAMERON	USA	Biomedical Research and Research Training	000	6	3/29/2016	NON-COMPETING CONTINUATION	-$93,226
2016	2015	UNIVERSITY OF TEXAS RIO GRANDE VALLEY (UTRGV)	1201 W. UNIVERSITY DR	EDINBURG	TX	78539	HIDALGO	USA	Biomedical Research and Research Training	001	7	3/30/2016	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$93,226
														Subtotal = $98,750

Issue Date FY: 2015 ( Subtotal = $100,451 )
2015	2015	UNIVERSITY OF TEXAS AT BROWNSVILLE	80 FORT BROWN	BROWNSVILLE	TX	78520	CAMERON	USA	Biomedical Research and Research Training	000	6	9/4/2015	NON-COMPETING CONTINUATION	$100,451
														Subtotal = $100,451

Issue Date FY: 2014 ( Subtotal = $99,709 )
2014	2014	UNIVERSITY OF TEXAS AT BROWNSVILLE	80 FORT BROWN	BROWNSVILLE	TX	78520	CAMERON	USA	Biomedical Research and Research Training	000	5	8/11/2014	NON-COMPETING CONTINUATION	$99,709
														Subtotal = $99,709

Issue Date FY: 2013 ( Subtotal = $98,990 )
2013	2013	UNIVERSITY OF TEXAS AT BROWNSVILLE	80 FORT BROWN	BROWNSVILLE	TX	78520	CAMERON	USA	Biomedical Research and Research Training	000	4	8/8/2013	COMPETING CONTINUATION	$98,990
														Subtotal = $98,990

Issue Date FY: 2010 ( Subtotal = $102,169 )
2010	2010	UNIVERSITY OF TEXAS AT BROWNSVILLE	80 FORT BROWN	BROWNSVILLE	TX	78520	CAMERON	USA	Biomedical Research and Research Training	000	3	5/5/2010	NON-COMPETING CONTINUATION	$102,169
														Subtotal = $102,169

Issue Date FY: 2009 ( Subtotal = $101,753 )
2009	2009	UNIVERSITY OF TEXAS AT BROWNSVILLE	80 FORT BROWN	BROWNSVILLE	TX	78520	CAMERON	USA	Biomedical Research and Research Training	000	2	3/26/2009	NON-COMPETING CONTINUATION	$101,753
														Subtotal = $101,753

Issue Date FY: 2008 ( Subtotal = $101,349 )
2008	2008	UNIVERSITY OF TEXAS AT BROWNSVILLE	80 FORT BROWN	BROWNSVILLE	TX	78520	CAMERON	USA	Biomedical Research and Research Training	000	1	5/1/2008	NEW	$101,349
														Subtotal = $101,349

Grand Total All Awards = $708,722

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Thermodynamics and kinetics of DNA-ligand binding probed by DNA overstretching

Award Number: SC3GM083779

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: 05/01/2008

PERIOD OF PERFORMANCE END DATE: 07/31/2017

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