Biopolym. Cell. 2009; 25(2):133-141.
Molecular Biophysics
Hydrophobic contribution to the free energy of complexation of aromatic ligands with DNA
1Kostjukov V. V., 1Khomutova N. M., 1Lantushenko A. O., 1Evstigneev M. P.
  1. Sevastopol National Technical University
    33, Universytetska Str., Sevastopol, Ukraine, 99053


The hydrophobic component of complexation energy of double-stranded DNA with biologically active aromatic compounds was calculated using two semi-empirical methods – correlations of hydrophobic energy with changes of a heat capacity (ΔCp) and solvent-accessible surface area (SASA). These surface areas were calculated for free ligands and DNA oligomers, unwound DNA duplexes and DNA-ligand complexes. The changes of polar and non-polar SASAs of molecules upon binding ligands to DNA were found. The hydrophobic contribution at both complexation stages were calculated. It was shown that the calculation of hydrophobic energy by SASA method is more correct than (ΔCp) method for DNA-binding ligands.
Keywords: double-stranded DNA, aromatic ligand, hydrophobic contribution, solvent-accessible surface area


[1] Chu E., DeVita V. T. Physicians' cancer chemotherapy drug manual London: Jones and Bartlett publ., 2003 512 p.
[2] Neidle S., Waring M. J. Molecular aspects of anti-cancer drug action London: Macmillan, 1983 483 p.
[3] Pullman B. Molecular mechanism of specifity in DNA-antitumor drug interactions Adv. Drug Res 1989 18:2– 112.
[4] Graves D. E., Velea L. M. Intercalative binding of small molecules to nucleic acids Curr. Org. Chem 2000 4, N 9 P. 915–928.
[5] Sartorius J., Schneider H.-J. Intercalation mechanisms with ds-DNA: binding modes and energy contributions with benzene, naphthalene, quinoline and indole derivatives including some antimalarials J. Chem. Soc. Perkin Trans. 2 1997 P. 2319–2327.
[6] Reha D., Kabelac M., Ryjacek F., Sponer J., Sponer J. E., Elstner M., Suhai S., Hobza P. Intercalators. 1. Nature of stacking interactions between intercalators (ethidium, daunomycin, ellipticine, and 4',6-diaminide-2-phenylindole) and DNA base pairs. Ab initio quantum chemical, density functional theory, and empirical potential study J. Amer. Chem. Soc 2002 124, N 13:3366–3376.
[7] Kubar T., Hanus M., Ryjacek F., Hobza P. Binding of cationic and neutral phenanthridine intercalators to a DNA oligomer is controlled by dispersion energy: quantum chemical calculations and molecular mechanics simulations Chem. Eur. J 2006 12:280–290.
[8] Luo R., Gilson H. S. R., Potter M. J., Gilson M. K. The physical basis of nucleic acid base stacking in water Biophys. J 2001 80, N 1:140–148.
[9] Medhi C., Mitchell J. B. O., Price S. L., Tabor A. B. Electrostatic factors in DNA intercalation Biopolymers 1999 52:84–93.
[10] Lane A. N., Jenkins T. C. Thermodynamics of nucleic acids and their interactions with ligands Quart. Rev. Biophys 2000 33, N 3:255–306.
[11] Ren J., Jenkins T. C., Chaires J. B. Energetics of DNA intercalation reactions Biochemistry 2000 39, N 29 P. 8439–8447.
[12] Meirovitch H. Recent developments in methodologies for calculating the entropy and free energy of biological systems by computer simulation Curr. Opin. Struct. Biol 2007 17:181–186.
[13] Sokolov V. F., Chuev G. N. A probabilistic method for the calculation of energy of hydrophobic interactions Biophysics 2006 51, N 2:207–213.
[14] Lin M. S., Fawzi N. L., Head-Gordon T. Hydrophobic potential of mean force as a solvation function for protein structure prediction Structure – 2007 15:727–740.
[15] Sharp K. A., Nicholls A., Fine R. F., Honig B. Reconciling the magnitude of the microscopic and macroscopic hydrophobic effects Science 1991 252, N 5002:106–109.
[16] Dill K. A., Privalov P. L., Gill S. J., Murphy K. P. The meaning of hydrophobicity Science 1990 250, N 4978 P. 297–298.
[17] Baginski M., Fogolari F., Briggs J. M. Electrostatic and non-electrostatic contributions to the binding free energies of anthracycline antibiotics to DNA J. Mol. Biol 1997 274, N 2:253–267.
[18] Berman H. M., Westbrook J., Feng Z., Gilliland G., Bhat T. N., Weissig H., Shindyalov I. N., Bourne P. E. The protein data bank Nucl. Acids Res 2000 28, N 1:235–242.
[19] Cheatham T. E., Cicplak P., Kollman P. A. A modified version of the Cornell et al. force field with improved sugar pucker phases and helical repeat J. Biomol. Struct. and Dyn 1999 16, N 4:845–862.
[20] Brana M. F., Cacho M., Gradillas A., Pascual-Teresa B., Ramos A. Intercalators as anticancer drugs Curr. Pharm. Des 2001 7, N 17:1745–1780.
[21] Neidle S., Pearl L. H., Herzyk P., Berman H. M. A molecular model for proflavine-DNA intercalation Nucl. Acids Res 1988 16, N 18:8999–9016.
[22] Davies D. B., Djimant L. N., Baranovsky S. F., Veselkov A. N. 1H-NMR determination of the thermodynamics of drug complexation with single-stranded and double-stranded oligonucleotides in solution: ethidium bromide complexation with the deoxytetranucleotides 5'-d(ApCpGpT), 5'-d(ApGpCpT), and 5'-d(TpGpCpA) Biopolymers 1997 42, N 3:285–295.
[23] Snyder J. G., Hartman N. G., D'Estantoit B. L., Kennard O., Remeta D. P., Breslauer K. J. Binding of actinomycin D to DNA: Evidence for a nonclassical high-affinity binding mode that does not require GpC sites Proc. Nat. Acad. Sci. USA 1989 86, N 11:3968–3972.
[24] Brunger A. T. X-PLOR. A system for X-ray crystallography and NMR–Yale: Univ. Press, 1992 382 p.
[25] Misra V. K., Honig B. On the magnitude of the electrostatic contribution to Ligand-DNA interactions Proc. Natl Acad. Sci. USA 1995 92, N 10:4691–4695.
[26] Feigon J., Denny W. A., Leupin W., Kearns D. R. Interactions of antitumor drugs with natural DNA: 1H NMR study of binding mode and kinetics J. Med. Chem 1984 27, N 4 P. 450–465.
[27] Waring M. Variation of the supercoils in closed circular DNA by binding of antibiotics and drugs: evidence for molecular models involving intercalation J. Mol. Biol 1970 54(2):247–279.
[28] Kapuscinski J., Darzynkiewicz Z., Traganos F., Melamed M. R. Interactions of a new antitumor agent, 1,4-dihydroxy-5,8bis[[2-[(2-hydroxyethyl)amino]-ethyl]amino]-9,10-anthracenedione, with nucleic acids Biochem. Pharm 1981 30, N 3:231–240.
[29] Yang X.-L., Wang A. H.-J. Structural studies of atom-specific anticancer drugs acting on DNA Pharm. Ther 1999 83, N 3:181–215.
[30] Searle M. S. NMR studies of drug-DNA interactions Progr. NMR Spectr 1993 25, N 5:403–480.
[31] Makhatadze G. I., Privalov P. L. Energetics of protein structure Adv. Protein Chem 1995 47:307–425.
[32] Janin J. Angstroms and calories Structure 1997 5, N 4 P. 473–479.
[33] Noskov S. Yu., Lim C. Free energy decomposition of proteinprotein interactions. Biophys. J 2001 81,N 2:737–750.
[34] Friedman R. A., Honig B. A Free energy analysis of nucleic acid base stacking in aqueous solution Biophys. J 1995 69, N 4:1528–1535.
[35] Fraczkiewicz R., Braun W. Exact and efficient analytical calcu lation of the accessible surface areas and their gradients for macromolecules J. Comp. Chem 1998 19, N 3:319–333.
[36] Lee B., Richards F. M. The interpretation of protein structures: estimation of static accessibility J. Mol. Biol 1971 55, N 3:379–400.
[37] Ha J.-H., Spolar R. S., Record M. T. Role of the hydrophobic effect in stability of site-specific Protein-DNA complexes J. Mol. Biol 1989 209, N 4 P.801–816.
[38] Spolar R. S., Record M. T. Coupling of local folding to sitespecific binding of proteins to DNA Science 1994 263, N 5148:777–784.
[39] Baldwin R. L. Temperature dependence of the hydrophobic interaction in protein folding Proc. Nat. Acad. Sci. USA 1986 83, N 21:8069–8072.
[40] Kostjukov V. V., Khomytova N. M., Evstigneev M. P. «Calibration» of hydrophobic contribution to the free energy of reaction of aromatic molecules complexation in solution Russ. J. Phys. Chem. A 2009 (in press).