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Updated: Jul 9, 2026
Analyzing Protein Architectures and Protein-Ligand Complexes by Integrative Structural Mass Spectrometry
Published on: October 15, 2018
Molecular modeling and biophysical analysis of the c-MYC NHE-III1 silencer element
Derek J Cashman1, Robert Buscaglia, Matthew W Freyer
1Department of Chemistry and Biochemistry, Northern Arizona University, PO Box 5698, South Beaver Street, Flagstaff, AZ 86011-5698, USA.
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-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.
Insights
Molecular models of the c-MYC nuclease hypersensitivity element III(1) were created to study G-Quadruplex and i-Motif structures. These models help understand how porphyrin drugs bind to oncogene promoter regions.
Area of Science:
- Structural biology
- Computational chemistry
- Molecular modeling
Background:
- G-Quadruplex and i-Motif structures in oncogene promoter regions are potential therapeutic targets.
- The c-MYC NHE-III(1) is a key regulatory element with potential for drug targeting.
Purpose of the Study:
- To create molecular models of the c-MYC NHE-III(1) G-Quadruplex and i-Motif structures.
- To investigate the binding interactions of porphyrin compounds with these DNA structures.
Main Methods:
- Molecular modeling of G-Quadruplex and i-Motif conformers.
- In silico prediction of loop structures.
- Docking of porphyrin analogs (TMPyP4, TMPyP2, TMPyP3).
- Molecular dynamics simulations and interaction energy calculations.
Main Results:
- Models of the c-MYC NHE-III(1) incorporating G-Quadruplex and i-Motif structures were generated.
- Porphyrin compounds were docked to various sites within the NHE models.
- Molecular dynamics simulations provided insights into drug-DNA interactions.
Conclusions:
- The study provides detailed molecular models for understanding G-Quadruplex and i-Motif interactions within the c-MYC NHE-III(1).
- These models facilitate the investigation of cationic porphyrins as potential modulators of oncogene activity.
