The research combines computer simulation (energy optimization/expansion techniques, Monte-Carlo calculations, and normal-mode analysis) with a new naturally discrete model of DMAto examine the configurations and properties of supercoiled DMA,a topologically constrained form of the double helix subject to higher-order folding and compensatory strand twisting and the way that DMAexists in living cells. Base sequence-dependentfeatures of the long, threadlike polymer are incorporated in the theory and treated by numerical simulations. By combining analytical studies with computer simulations, we obtain complementary information and have a series of built-in checks and balances for assessing the significance of our findings. The computational results stimulate new theoretical developments, which in turn can be used to assess the validity of the calculations. The effects of the sugar-phosphate backbone and local chemical environment are treated implicitly with knowledge-based potentials extracted from high-resolution structures of double-helical DMAand, in representative cases, with explicit treatment of long-range forces. Our immediate goals are to study the sequence-dependent biophysical properties of DMA minicircles and loops and to establish the physico-chemical basis of in-vivo looping. The proposed studies aim to clarify the role of primary chemical features (base sequence), ligand binding (proteins), and levels of supercoiling (imposed constraints on base-pair positioning) on the overall folding of the double helix. We will extend our studies of DMA loops tethered to the Lac represser protein with the aim of gathering new insights into the role of the molecular assembly in the regulation of transcription and its potential applicability as a model of eukaryotic insulators. A second goal is to gain insight into the effect of DMAsequence and supercoiling on protein binding and consequent cellular function. Other issues to be addressed include: (1) the role of local sequence-dependent structure and ligand binding on large-scale configurational transitions of spatially constrained duplexes;(2) the competing effects of multiple proteins on the configurational properties of supercoiled molecules;and (3) the interplay of local and global structure in supercoiling dynamics.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM034809-24
Application #
7921602
Study Section
Macromolecular Structure and Function B Study Section (MSFB)
Program Officer
Preusch, Peter C
Project Start
1985-08-01
Project End
2011-08-31
Budget Start
2010-09-01
Budget End
2011-08-31
Support Year
24
Fiscal Year
2010
Total Cost
$223,312
Indirect Cost
Name
Rutgers University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
001912864
City
New Brunswick
State
NJ
Country
United States
Zip Code
08901
Xu, Fei; Zheng, Hongning; Clauvelin, Nicolas et al. (2017) Parallels between DNA and collagen - comparing elastic models of the double and triple helix. Sci Rep 7:12802
Nizovtseva, Ekaterina V; Todolli, Stefjord; Olson, Wilma K et al. (2017) Towards quantitative analysis of gene regulation by enhancers. Epigenomics 9:1219-1231
Todolli, Stefjord; Perez, Pamela J; Clauvelin, Nicolas et al. (2017) Contributions of Sequence to the Higher-Order Structures of DNA. Biophys J 112:416-426
Nizovtseva, Ekaterina V; Clauvelin, Nicolas; Todolli, Stefjord et al. (2017) Nucleosome-free DNA regions differentially affect distant communication in chromatin. Nucleic Acids Res 45:3059-3067
Perez, Pamela J; Olson, Wilma K (2016) Insights into Genome Architecture Deduced from the Properties of Short Lac Repressor-mediated DNA Loops. Biophys Rev 8:135-144
Lu, Xiang-Jun; Bussemaker, Harmen J; Olson, Wilma K (2015) DSSR: an integrated software tool for dissecting the spatial structure of RNA. Nucleic Acids Res 43:e142
Clauvelin, N; Lo, P; Kulaeva, O I et al. (2015) Nucleosome positioning and composition modulate in silico chromatin flexibility. J Phys Condens Matter 27:064112
Wei, Juan; Czapla, Luke; Grosner, Michael A et al. (2014) DNA topology confers sequence specificity to nonspecific architectural proteins. Proc Natl Acad Sci U S A 111:16742-7
Yusufaly, Tahir I; Li, Yun; Singh, Gautam et al. (2014) Arginine-phosphate salt bridges between histones and DNA: intermolecular actuators that control nucleosome architecture. J Chem Phys 141:165102
Clauvelin, Nicolas; Olson, Wilma K; Tobias, Irwin (2014) Effect of the boundary conditions and influence of the rotational inertia on the vibrational modes of an elastic ring. J Elast 115:193-224

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