Partition of thermodynamic energies of drug–DNA complexation

Abstract

We report a computation methodology, which leads to the ability to partition the Gibb's free energy for the complexation reaction of aromatic drug molecules with DNA. Using this approach, it is now possible to calculate the absolute values of the energy contributions of various physical factors to the DNA binding process, whose summation gives a value that is reasonably close to the experimentally measured Gibb's free energy of binding. Application of the methodology to binding of various aromatic drugs with DNA provides an answer to the question "What forces are the main contributors to the stabilization of aromatic ligand-DNA complexes?"

General features of the energetics of complex formation between ligand and nucleic acids

“…The most heretofore complete decomposition of Gibbs free energy into energetic components may be presented in the form of the following equa tion [5][6][7][8][9][10][11]: (1) where superscripts "solv" and "im" denote respec tively interaction with aqueous medium and interac tion of molecules in complex (in vacuo); ΔG total denotes the sum of theoretically calculated energetic components; ΔG conf -energetic contribution from conformational changes in molecules upon complex formation; ΔG VDW , ΔG EL and ΔG HYD -contributions from van der Waals (VDW), electrostatic (EL) and hydrophobic (HYD) interactions; ΔG HB -contribu tion from the energetics of loss of hydrogen bonds (HB) "to water" and formation of new inter molecular HB in the complex ΔG entr = ΔG TR + ΔG VIB1 + ΔG VIB2 -entropic contribution con ditioned by the change of the total number of degrees of freedom of the system: translational + rotational -ΔG TR (TR), vibrations of chemical bonds -ΔG VIB1 (VIB1) and residual mechanical vibrations of ligand in the binding site -ΔG VIB2 (VIB2). (Equation (1) in explicit form does not take into account two more components -polyelectrolytic contribution and con tribution from "charge transfer", their magnitude in aqueous medium turns out to be essentially smaller as compared with the rest of energetic components [5].)…”

“…(Equation (1) in explicit form does not take into account two more components -polyelectrolytic contribution and con tribution from "charge transfer", their magnitude in aqueous medium turns out to be essentially smaller as compared with the rest of energetic components [5].) Inasmuch as reliable separation of the energy of HB and EL factors is problematic, in the quality of an index of efficiency of hydrogen bonding it is expedient to use not Gibbs energy but the number of intermolec ular hydrogen bonds in complex (N im instead of Δ and the change in the number of hydrogen bonds "to water" upon complex formation (ΔN solv instead of Δ (see more detailed discussion of the specifics of estimation of the constituent from hydro gen bonds in works [5,8]). …”

“…Calculation and analysis of each component in equation (1) presents in itself an autonomous prob lem-a general notion about the problematics of such calculations may be obtained from primary source works [5][6][7][8][9]11] or from monograph [10]. Let us note only that the main condition imposed on equation (1) comes to be coincidence of total calculated energy ΔG total with experimentally measured ΔG exp -in the framework of admissible inaccuracy.…”

“…For complex formation of biologically active com pounds with nucleic acids (NAs) the methodology of energetic analysis was developed most systematically first in works [1][2][3][4], and later by authors of the given work [5][6][7][8][9][10]. By the present day for DNA intercalators [2,3,[5][6][7]10], compounds binding in the DNA minor groove (MGB) [4,8,10], some RNA binding ligands [9,10] and aromatic π stacking [10,11] the energetic analysis factually was already executed.…”

“…By the present day for DNA intercalators [2,3,[5][6][7]10], compounds binding in the DNA minor groove (MGB) [4,8,10], some RNA binding ligands [9,10] and aromatic π stacking [10,11] the energetic analysis factually was already executed. The aim of the given work is analysis and revelation of the regularities of distribution of energetics over various physical fac tors giving a contribution into total Gibbs energy of reactions of binding of ligands with various types of bioreceptors, on the basis of material accumulated in literature.…”