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

Derek J. Cashman, Robert Buscaglia, Matthew W. Freyer, Jamie Dettler, Laurence Hurley, Edwin A. Lewis

Research output: Contribution to journalArticle

23 Citations (Scopus)

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(A2 C4)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.

Original languageEnglish (US)
Pages (from-to)93-101
Number of pages9
JournalJournal of Molecular Modeling
Volume14
Issue number2
DOIs
StatePublished - Feb 2008

Fingerprint

Transcriptional Silencer Elements
silencers
nuclease
G-Quadruplexes
Molecular modeling
Cytosine
Porphyrins
porphyrins
oncogenes
Hypersensitivity
deoxyribonucleic acid
Oncogenes
Nuclear magnetic resonance
nuclear magnetic resonance
DNA sequences
interactions
Genetic Promoter Regions
Isomers
Molecular Models
Molecular dynamics

Keywords

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

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Biochemistry
  • Biophysics
  • Computer Science Applications
  • Computational Theory and Mathematics

Cite this

Molecular modeling and biophysical analysis of the c-MYC NHE-III1 silencer element. / Cashman, Derek J.; Buscaglia, Robert; Freyer, Matthew W.; Dettler, Jamie; Hurley, Laurence; Lewis, Edwin A.

In: Journal of Molecular Modeling, Vol. 14, No. 2, 02.2008, p. 93-101.

Research output: Contribution to journalArticle

Cashman, Derek J. ; Buscaglia, Robert ; Freyer, Matthew W. ; Dettler, Jamie ; Hurley, Laurence ; Lewis, Edwin A. / Molecular modeling and biophysical analysis of the c-MYC NHE-III1 silencer element. In: Journal of Molecular Modeling. 2008 ; Vol. 14, No. 2. pp. 93-101.
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