The three objectives of this theoretical study of DNA supercoiling are: (1) Developing a general dynamic scheme capable of millisecond simulations for a macroscopic polymer subject to hydrodynamics modeled by curve-fitting techniques. (2) Developing an extension of the homogeneous, elastic rod energy model for dynamic simulations of DNA to incorporate sequence and protein-binding effects. (3) Studying systematically the global structural and dynamic features of DNA associated with site juxtaposition, the rate at which two sites along the DNA come into close spatial proximity as a result of supercoiling; this general problem has many applications to genetic processes where juxtaposition is a prerequisite for the reaction and where DNA supercoiling plays mechanistic roles, such as transcription regulation, recombination, and topoisomerase activity. Unfortunately, it is very difficult to study these fast processes by instrumentation. Our juxtaposition simulations will be performed for average-sequence DNA, plasmids of specific composition, and DNA bound to proteins, with a major focus on site-synapsis kinetics in the recombination of resolvase. The studies will help clarify the role of supercoiling in processes involving supercoiled DNA and DNA/protein interactions: How does supercoiling enhance juxtaposition with respect to linear DNA, and how do juxtaposition times depend on the site separation, DNA length, salt concentration, DNA sequence, and bound proteins? Simulations will also address specific biological hypotheses of supercoiled-directed mechanisms concerning the experimentally-measured dependence of synapsis on the superhelical density, the failure of synapsis for nicked circular DNA, the indispensability of supercoiling in site-specific recombinations where three sites synapse but not two, the orientation selectivity in recombination reactions that depend on supercoiling, the fast and topologically-specific juxtaposition in resolvase, and the kinetics of site synapsis in resolvase. New modeling and simulation protocols for studying biologically interesting processes of supercoiled DNA in solution that are large-scale and long-time will also result. The global characteristics of the double helix explored here - interactions among distant DNA sites, supercoiling dynamics and energetics - play important roles in the action of the metabolically essential enzymes that interact with DNA. Further progress in our understanding of superhelicity has many practical benefits: Understanding the dependence of juxtaposition rates on external and internal factors might also ultimately help design conditions to enhance recognition among sites within long DNA and hence also between DNA and proteins. The fundamental importance of DNA topoisomerases associated with supercoiling and knotting has led to much research on topoisomerase inhibitors that act as anticancer or antibacterial drugs. Thus, any new structural and dynamic information on supercoiling and DNA-protein interactions may ultimately contribute to these pharmaceutical applications.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM055164-01A2
Application #
2701796
Study Section
Molecular and Cellular Biophysics Study Section (BBCA)
Project Start
1998-09-01
Project End
2002-08-31
Budget Start
1998-09-01
Budget End
1999-08-31
Support Year
1
Fiscal Year
1998
Total Cost
Indirect Cost
Name
New York University
Department
Type
Organized Research Units
DUNS #
004514360
City
New York
State
NY
Country
United States
Zip Code
10012
Bascom, Gavin D; Schlick, Tamar (2018) Chromatin Fiber Folding Directed by Cooperative Histone Tail Acetylation and Linker Histone Binding. Biophys J 114:2376-2385
Rao, Suhas S P; Huang, Su-Chen; Glenn St Hilaire, Brian et al. (2017) Cohesin Loss Eliminates All Loop Domains. Cell 171:305-320.e24
Bascom, Gavin; Schlick, Tamar (2017) Linking Chromatin Fibers to Gene Folding by Hierarchical Looping. Biophys J 112:434-445
PeriĊĦi?, Ognjen; Schlick, Tamar (2017) Dependence of the Linker Histone and Chromatin Condensation on the Nucleosome Environment. J Phys Chem B 121:7823-7832
Schlick, Tamar; Loew, Leslie (2017) Unraveling Genome Biophysics. Biophys J 112:E1-E2
Bascom, Gavin D; Kim, Taejin; Schlick, Tamar (2017) Kilobase Pair Chromatin Fiber Contacts Promoted by Living-System-Like DNA Linker Length Distributions and Nucleosome Depletion. J Phys Chem B 121:3882-3894
Bascom, Gavin D; Sanbonmatsu, Karissa Y; Schlick, Tamar (2016) Mesoscale Modeling Reveals Hierarchical Looping of Chromatin Fibers Near Gene Regulatory Elements. J Phys Chem B 120:8642-53
Luque, Antoni; Ozer, Gungor; Schlick, Tamar (2016) Correlation among DNA Linker Length, Linker Histone Concentration, and Histone Tails in Chromatin. Biophys J 110:2309-2319
Grigoryev, Sergei A; Bascom, Gavin; Buckwalter, Jenna M et al. (2016) Hierarchical looping of zigzag nucleosome chains in metaphase chromosomes. Proc Natl Acad Sci U S A 113:1238-43
Ozer, Gungor; Collepardo-Guevara, Rosana; Schlick, Tamar (2015) Forced unraveling of chromatin fibers with nonuniform linker DNA lengths. J Phys Condens Matter 27:064113

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