The object of this project is to compute the conformations of segments of double and single stranded DNA modified at a single central site by various covalently linked polycyclic aromatic carcinogens. The calculated conformations will be compared to available data on mutagenicity and carcinogenicity of the particular lesion, in order to seek a general relationship between deformations in DNA and the biological responses to them. The base sequences to be investigated will be largely those that have been implicated as mutagenic sequences in bacterial systems, including especially the alternating G-C's. Our computational method proceeds in distinct phases. First we calculate the most favorable conformations of a carcinogen modified dinucleoside-monophosphate, using minimized semi- empirical potential energy methods with about 4000 trails. The low energy conformations from this stage are then incorporated in single stranded tetramers with the added residues in the A, B, Z or other helical conformation, and the energy is again minimized. A selection is again made on energetic grounds, and the lowest energy forms are further incorporated into larger polymers for final energy minimization. New search strategies will be devised and tested in addition to the above, and employed if proven useful. We will search for novel unmodified single stranded polymers by combining stepwise the low energy dimer subunits and minimizing the energy. Novel unmodified duplexes will be sought from the single stranded forms. The important computed structures will then be employed in addition to the A, B and Z helices in the carcinogen studies. Furthermore, we will investigate single stranded trimers, modified at the central based, as a conformational building block. Unusual carcinogen modified duplex or partly denatured forms, suggested from the dimer and trimer studies, such as bulges, cruciforms and B-Z junctions, will be sought both computationally and with the Evans and Sutherland Interactive Computer Graphics System. In the above studies, we shall employ potentials and programs that already have been developed and are in working order. At the same time, we will also work on some basic areas of methodology, including the development of a new cartesian space program, specific incorporation of metals ions and the investigations of problems associated with the minimization method. Furthermore, we may be able to proceed to molecular dynamics in the proposed project period, which may enable us to locate important new forms and paths between conformations that are significant for carcinogen-modified DNA.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Biophysics and Biophysical Chemistry A Study Section (BBCA)
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New York University
Schools of Arts and Sciences
New York
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Fu, Iwen; Cai, Yuqin; Geacintov, Nicholas E et al. (2017) Nucleosome Histone Tail Conformation and Dynamics: Impacts of Lysine Acetylation and a Nearby Minor Groove Benzo[a]pyrene-Derived Lesion. Biochemistry 56:1963-1973
Fu, Iwen; Cai, Yuqin; Zhang, Yingkai et al. (2016) Entrapment of a Histone Tail by a DNA Lesion in a Nucleosome Suggests the Lesion Impacts Epigenetic Marking: A Molecular Dynamics Study. Biochemistry 55:239-42
Cai, Yuqin; Kropachev, Konstantin; Terzidis, Michael A et al. (2015) Differences in the Access of Lesions to the Nucleotide Excision Repair Machinery in Nucleosomes. Biochemistry 54:4181-5
Liu, Zhi; Ding, Shuang; Kropachev, Konstantin et al. (2015) Resistance to Nucleotide Excision Repair of Bulky Guanine Adducts Opposite Abasic Sites in DNA Duplexes and Relationships between Structure and Function. PLoS One 10:e0137124
Mu, Hong; Geacintov, Nicholas E; Zhang, Yingkai et al. (2015) Recognition of Damaged DNA for Nucleotide Excision Repair: A Correlated Motion Mechanism with a Mismatched cis-syn Thymine Dimer Lesion. Biochemistry 54:5263-7
Lior-Hoffmann, Lee; Ding, Shuang; Geacintov, Nicholas E et al. (2014) Structural and dynamic characterization of polymerase ?'s minor groove lesion processing reveals how adduct topology impacts fidelity. Biochemistry 53:5683-91
Rodríguez, Fabián A; Liu, Zhi; Lin, Chin H et al. (2014) Nuclear magnetic resonance studies of an N2-guanine adduct derived from the tumorigen dibenzo[a,l]pyrene in DNA: impact of adduct stereochemistry, size, and local DNA sequence on solution conformations. Biochemistry 53:1827-41
Kropachev, Konstantin; Ding, Shuang; Terzidis, Michael A et al. (2014) Structural basis for the recognition of diastereomeric 5',8-cyclo-2'-deoxypurine lesions by the human nucleotide excision repair system. Nucleic Acids Res 42:5020-32
Lee, Yuan-Cho; Cai, Yuqin; Mu, Hong et al. (2014) The relationships between XPC binding to conformationally diverse DNA adducts and their excision by the human NER system: is there a correlation? DNA Repair (Amst) 19:55-63
Cai, Yuqin; Geacintov, Nicholas E; Broyde, Suse (2014) Ribonucleotides as nucleotide excision repair substrates. DNA Repair (Amst) 13:55-60

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