Molecular dynamic simulation and DFT study on the Drug-DNA interaction; Crocetin as an anti-cancer and DNA...

Area of Science:

• Computational Chemistry
• Molecular Biology
• Pharmacology

Background:

• Crocetin is a natural compound with demonstrated anti-cancer properties.
• Understanding drug-DNA interactions is crucial for developing effective cancer therapies.
• The Dickerson dodecamer (d(CGCGAATTCGCG)2) is a well-characterized DNA sequence model.

Purpose of the Study:

• To investigate the molecular interactions between Crocetin and Dickerson DNA.
• To identify the primary binding sites and interaction types.
• To elucidate the thermodynamic and quantum mechanical basis of Crocetin-DNA complexation.

Main Methods:

• 25 ns molecular dynamic simulations of Crocetin and Dickerson DNA in aqueous solution.
• Analysis of binding energy, focusing on van der Waals and hydrogen bonding.
• Thermodynamic calculations (ΔG) to assess interaction stability.
• Radial distribution functions (RDFs) to identify hydrogen bond formation.
• Quantum Theory of Atoms in Molecules (QTAIM) for electron density analysis.

Main Results:

• Van der Waals interactions are dominant, particularly involving oxygen and hydrogen atoms between Crocetin and DNA.
• Maximum stabilizing interactions (ΔG) occur in the S1 region, with minimum in S3, indicating the minor groove as a probable binding site.
• New hydrogen bonds (PO⋯HO and NH⋯OC) form between Crocetin and DNA, evidenced by RDF peaks.
• QTAIM analysis suggests Crocetin may induce DNA instability via H-bond denaturation.
• Dispersion interactions significantly contribute to the overall binding energy (-148.76 kcal/mol).

Conclusions:

• Crocetin binds to Dickerson DNA primarily through van der Waals forces and hydrogen bonding in the minor groove.
• The formation of new hydrogen bonds appears to be a key factor in Crocetin's anti-cancer activity.
• Crocetin-induced DNA denaturation may contribute to its therapeutic effect.