Molecular modeling and biophysical analysis of the c-MYC NHE-III1 silencer element
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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-III1 (nuclease hypersensitivity element III1) 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(A2C4)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.
KeywordsG-quadruplex i-Motif Oncogenes c-MYC Silencer element NHE III1 TMPyP4
The authors would like to thank Drs. Jonathan (Brad) Chaires of the University of Louisville, James G. Brown Cancer Center, and David Wilson of Georgia State University, Department of Chemistry and Biochemistry for their many helpful discussions. Funding for this research was received from Northern Arizona University Proposition 301 TRIF Grant to E.A.L. and Arizona Biomedical Research Commission (0014 to L.H.H. and E.A.L. and 0015 to E.A.L. and L.H.H.).
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