Molecular modeling and biophysical analysis of the c-MYC NHE-III1 silencer element.
G-Quadruplex and i-Motif-forming sequences in the promoter regions of several oncogenes show promise as targets for the regulation of oncogenes. In this study, molecular models were created for the c-MYC NHE-III(1) (nuclease hypersensitivity element III(1)) from two 39-base complementary sequences. The NHE modeled here consists of single folded conformers of the polypurine intramolecular G-Quadruplex and the polypyrimidine intramolecular i-Motif structures, flanked by short duplex DNA sequences. The G-Quadruplex was based on published NMR structural data for the c-MYC 1:2:1 loop isomer. The i-Motif structure is theoretical (with five cytosine-cytosine pairs), where the central intercalated cytosine core interactions are based on NMR structural data obtained for a tetramolecular [d(A(2)C(4))(4)] model i-Motif. The loop structures are in silico predictions of the c-MYC i-motif loops. The porphyrin meso-tetra(N-methyl-4-pyridyl)porphine (TMPyP4), as well as the ortho and meta analogs TMPyP2 and TMPyP3, were docked to six different locations in the complete c-MYC NHE. Comparisons are made for drug binding to the NHE and the isolated G-Quadruplex and i-Motif structures. NHE models both with and without bound cationic porphyrin were simulated for 100 ps using molecular dynamics techniques, and the non-bonded interaction energies between the DNA and porphyrins calculated for all of the docking interactions.
Cashman
Derek J
DJ
Department of Chemistry and Biochemistry, Northern Arizona University, PO Box 5698, South Beaver Street, Flagstaff, AZ 86011-5698, USA.
Buscaglia
Robert
R
Freyer
Matthew W
MW
Dettler
Jamie
J
Hurley
Laurence H
LH
Lewis
Edwin A
EA
D001703:Biophysics; D004247:DNA / Q000737:chemistry; D015536:Down-Regulation / Q000502:physiology; D054856:G-Quadruplexes; D006801:Humans; D008958:Models, Molecular; D009690:Nucleic Acid Conformation; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics*; D037941:Silencer Elements, Transcriptional / Q000235:genetics*
C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D004247:DNA