Binding of Cationic and Neutral Phenanthridine Intercalators to a DNA Oligomer Is Controlled by Dispersion Energy: Quantum Chemical Calculations and Molecular Mechanics Simulations

Abstract

Correlated ab initio as well as semiempirical quantum chemical calculations and molecular dynamics simulations were used to study the intercalation of cationic ethidium, cationic 5-ethyl-6-phenylphenanthridinium and uncharged 3,8-diamino-6-phenylphenanthridine to DNA. The stabilization energy of the cationic intercalators is considerably larger than that of the uncharged one. The dominant energy contribution with all intercalators is represented by dispersion energy. In the case of the cationic intercalators, the electrostatic and charge-transfer terms are also important. The DeltaG of ethidium intercalation to DNA was estimated at -4.5 kcal mol(-1) and this value agrees well with the experimental result. Of six contributions to the final free energy, the interaction energy value is crucial. The intercalation process is governed by the non-covalent stacking (including charge-transfer) interaction while the hydrogen bonding between the ethidium amino groups and the DNA backbone is less important. This is confirmed by the evaluation of the interaction energy as well as by the calculation of the free energy change. The intercalation affects the macroscopic properties of DNA in terms of its flexibility. This explains the easier entry of another intercalator molecule in the vicinity of an existing intercalation site.

Electrostatic contribution to the energy of binding of aromatic ligands with DNA

“…24, EB from Ref. 20 and atomic charges of NOV, NOG, and AMD were calculated using the HyperChem program.…”

“…25 Using an explicit model in which the surrounding medium is an aqueous-salt solution, the molecular mechanics calculations of electrostatic interactions become very complicated because of the large number of molecules present in the system, the ambiguous nature of the distribution of counterions around the solute and the necessity of averaging over all possible configurations of the solvent. 9 For the same reasons, high-level quantum-mechanical calculations of ligand-DNA intermolecular interactions 26,27 are usually performed, except for one report, 20 without taking into account the aqueous-salt surroundings. In recent years many calculations 12,[15][16][17]25,[28][29][30] of the electrostatic energy of molecules and their complexes in aqueous-salt solution have been based on the solution of the nonlinear PoissonBoltzmann equation (NLPB method) using the finite difference method and the continuum solvent model.…”

Novel bis-phenanthridine derivatives with easily tunable linkers, study of their interactions with DNA and screening of antiproliferative activity

“…[1][2][3] In addition, it was shown that the chemical modulation of the ethidium substituents is a profitable option to tune the nucleic acid recognition properties of phenanthridine dyes. [4] Very recent reports about numerous applications point toward versatility of the phenanthridine core, [5][6][7][8][9] including even intriguing biological activity.…”

An Atomistic View of DNA Dynamics and Its Interaction with Small Binders: Insights from Molecular Dynamics and Principal Component Analysis

“…[35] for Hoechst and in Ref. [13] for the ethidium cation. The initial structures were solvated in a cubic periodic box, with a minimum buffer of 10 Å between any DNA or solute atom and the closest box edge.…”

“…Refs. [13][14][15] and references therein). We chose them as prototypes of two different mechanisms of interaction with the DNA double helix: Hoechst is a minor groove binder that binds selectively to A-rich part of the DNA sequence, while ethidium cation intercalates between base pairs (bps) without strong sequence specificity.…”