ISSN 1607-6729, Doklady Biochemistry and Biophysics, 2012, Vol. 446, pp. 223–228. © Pleiades Publishing, Ltd., 2012. Original Russian Text © D.S. Tarasov, M.Y. Ibragimova, E.D. Izotova, N.I. Akberova, R.I. Zhdanov, 2012, published in Doklady Akademii Nauk, 2012, Vol. 446, No. 2, pp. 226–231. 223 Interaction of DNA with low-molecular-weight ligands is of great theoretical and practical interest for molecular biology and pharmacology [1]. DNA is a target for peptide antibiotics, which bind in the minor groove, and for various antitumor drugs, which inter- act with it both covalently (through the formation of chemical bonds) and noncovalently (due to electro- static, van der Waals, and hydrophobic forces) [1, 2]. The presence of fatty acid residues in the fraction of lipids tightly bound to DNA has been shown for bac- teria, particularly for the gram-negative bacterium Pseudomonas aurantiaca [3]. The feasibility of interac- tion between DNA and natural fatty acids and a possi- ble regulatory role of the latter in gene expression was assumed and confirmed in a series of studies of the sta- bility of complexes formed by DNA oligomers with lipids, C18 fatty acids, and cholesterol, performed using the molecular mechanics approach [4–6]. Most of the results are based on the modeling of DNA–lipid complexes in vacuum and on the analysis of steady states of the complexes and isolated reagents [5, 6]. In a recent study [7], in which DNA–lipid complexes were investigated by molecular docking, the effects of the solvent were taken into account implicitly and the conformational flexibility of the DNA molecule was not taken into account at all [7]. Thus, the study of structure and conformational dynamics of DNA–fatty acid complexes is of undoubted interest. After the formation of a complex between DNA and lipids [8] (in particular, oleic acid [9]) was confirmed, no data on the spatial structure and molecular dynamics of such complexes have been published. Linoleic acid was chosen for the computer- aided experiments on the DNA binding because up to 70% of molecules of the natural phospholipid cardio- lipin in mitochondria contain four linoleic acid resi- dues. In this study, the complexes of a DNA oligonucle- otide consisting of 25 A–T base pairs (dA) 25 ⋅ (dT) 25 and linoleic acid (trans-9,12 octadecadienoic acid) in neutral and ionized forms were studied by the molec- ular dynamics method with the use of an “explicit sol- vent model.” It is shown that these complexes have a high conformational mobility. The free energy of for- mation of complexes between DNA and linoleic acid (8 and 13 kcal/mol for the anion and acid, respec- tively), were determined on the basis of molecular dynamics trajectories using the adaptive biasing force approach. It is shown that the proton of the acid is involved in hydrogen bonding with the phosphoryl group of DNA (the bond length in the equilibrium structure was 1.68 Å). Two main conformations of the complex of linoleic acid with DNA were identified. In the course of conformational dynamics, the formation and destruction of interactions between the polar and nonpolar residues of linoleic acid, on the one hand, and DNA, on the other, were observed. MATERIALS AND METHODS The Structure of the Ligands and Complexes The structural parameters of linoleic acid were obtained from the database HIC-Up [10]. The struc- ture of the double-stranded oligonucleotide consisting of 25 A–T pairs (dA) 25 ⋅ (dT) 25 was generated using the NAB utility of the AmberTools software package (AMBER 11, University of California, San Francisco, 2010). The coordinates of the atoms of complexes are given in accordance with the generally accepted nomenclature. To obtain the initial structures of com- plexes, the fatty acid was placed in the minor groove of DNA (in crystallographic configurations) using the VMD program. The complex was dissolved in a rect- angular periodicity cell using the TIP3P model of water molecules so that the distance between the peri- Molecular Dynamics and Free Energy of Binding of Oleic Acid to DNA in Aqueous Solutions D. S. Tarasov a , M. Y. Ibragimova a , E. D. Izotova a , N. I. Akberova a , and R. I. Zhdanov a, b Presented by Academician A.R. Khokhlov April 6, 2012 Received April 17, 2012 DOI: 10.1134/S1607672912050043 a Kazan (Volga) Federal University, ul. Kremlevskaya 18, Kazan, 420008 Russia b Institute of General Pathology and Pathophysiology, Russian Academy of Medical Sciences, ul. Baltiiskaya 8, Moscow, 125315 Russia BIOCHEMISTRY, BIOPHYSICS AND MOLECULAR BIOLOGY