Journal of Molecular Modeling

, Volume 14, Issue 2, pp 93–101 | Cite as

Molecular modeling and biophysical analysis of the c-MYC NHE-III1 silencer element

  • Derek J. Cashman
  • Robert Buscaglia
  • Matthew W. Freyer
  • Jamie Dettler
  • Laurence H. Hurley
  • Edwin A. Lewis
Original Paper

Abstract

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.

Figure

Molecular models of the average structure of the final 20 ps of the molecular dynamics simulation of the c-MYC NHE-III1 (nuclease hypersensitivity element III1) “silencer” element. The G-Quadruplex structure is at the top-center, and the i-Motif is at the bottom-center of each picture. a “Rotation #1” of the G-Quadruplex, with the T15 loop at the top and rear and the G19/A20 loop at the top and front of the picture. b “Rotation #2” of the G-Quadruplex, with the T15 loop at the top and front of the image, and the G19/A20 loop at the front and adjacent to the G-Quadruplex/i-Motif interface

Keywords

G-quadruplex i-Motif Oncogenes c-MYC Silencer element NHE III1 TMPyP4 

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Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Derek J. Cashman
    • 1
  • Robert Buscaglia
    • 1
  • Matthew W. Freyer
    • 1
  • Jamie Dettler
    • 1
  • Laurence H. Hurley
    • 2
    • 3
    • 4
    • 5
  • Edwin A. Lewis
    • 1
  1. 1.Department of Chemistry and BiochemistryNorthern Arizona UniversityFlagstaffUSA
  2. 2.College of PharmacyUniversity of ArizonaTucsonUSA
  3. 3.Arizona Cancer CenterTucsonUSA
  4. 4.BIO5 Institute for Collaborative BioresearchUniversity of ArizonaTucsonUSA
  5. 5.Department of ChemistryUniversity of ArizonaTucsonUSA

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