在核磁共振解析分子立體結構研究中提到由鎂二價離子配位結合的Mithramycin二聚物為與去氧核糖核甘酸被拓寬的副溝槽處結合的抑癌藥劑。由於向去氧核糖核甘酸特定之(G-C)．(G-C)序列中央部位結合，導致其螺旋構形重大的扭曲以便二聚物藥物的結合，例如介於TpA 階梯的扭曲以及因此而使去氧核糖核甘酸副溝槽由B-形式拓寬至A-形式。近來光譜學研究提出此具有兩個部分重疊之(GpC)鹼基配對結合位置之去氧核糖核甘酸*, (TAGCTAGCTA)2與同屬auerolic acid群組之相似結構抑癌藥物Mithramycin, Chromomycin A3間存在不同的結合化學劑量(配體:受體 = 2:1, 1:1)乃因藥物糖基上不同取代基造成的結構柔軟度為主影響。這裡，對於不同結合化學劑量的Mithramycin2-去氧核糖核甘酸進行分子動力模擬與自由能分析，並與上述實驗的結果作比較。在此研究所預測的結合自由能為-5.26 千
卡/莫耳，與實驗結果之-5.4千卡/莫耳有良好的一致性。兩組模型(
配體:受體 = 2:1, 1:1)均顯示熱焓為結合之驅動貢獻；而僅考慮熱焓與水溶液作用時，Mithramycin與此去氧核糖核甘酸為合作性。
進一步分析討論藥物的各部位與去氧核糖核甘酸之間的能量作用關係。

Recent NMR study has shown that the Mg2+-coordinated Mithramycin(MTR) dimer is a DNA-binding antitumor agent bound to a widened minor groove. Centering about the sequence-specific (G-C)·(G-C) binding site leads to the significant curvature of the helix conformation which facilitates binding of the dimer drug, such as the kink at the inter-mediate TpA step. Thus its minor groove is widened from B- to A-type.
For this DNA model, d(TAGCTAGCTA)2, which contains two partially overlapping potential binding sites(GpC), recent spectroscopic study shows that the different binding stoichiometry (ligand:receptor =2:1, 1:1) for Mithramycin and Chromomycin A3 (both of which belong to the aureolic acid group and are with similar structure). This results from the different conformational flexibility due to the nature of substituents in the saccharides of the both. Here, a molecular dynamics simulation study along with the analysis of free energy on different stoichiometry of
MTR2-DNA* is presented and compared with the experiment results described above. The binding free energy estimated in this study is -5.26 Kcal 1/mol which is in good greement with the experiment result,-5.4 Kcal 1/mol.The associations
are presumably enthalpy-driven for two binding model(ligand:receptor = 2:1, 1:1), and on the basis of
enthalpy considerations alone(including a salvation correction), the interaction of MTR with this DNA is somewhat cooperative. The interaction between each part of MTR and DNA* is further discussed in this study.

1.Sastry, M.; Fiala, R.; Patel, D. J.; Solution Structure of Mithramycin Dimers Bound to Partially Overlapping Sites on DNA; J. Mol. Biol. 1995, 251, 674-689.
2.Gao, X.; Mirau, P.; Patel, D. J.; Structure Refinement of Chromomycin Dimer – DNA Oligomer Complex in Solution; J. Mol. Biol. 1992, 223, 259-279.
3.Chakrabarti, S.; Bhattacharyya, B.; Dasgupta, D.; Interaction of Mithramycin and Chromomycin A3 with d(TAGCTAGCTA)2: Role of Sugars in Antibiotic – DNA Recognition; J. Phys. Chem. B, 2002, 106, 6947-6953.
4.United States National Library of Medicine (NLM); http://www.nlm.nih.gov/nlmhome.html
5.Gause, G. F. In Antibiotics III; Corocan, J. W., Hahn, F. E., Eds.; Springer-Verlag: Berlin and New York, 1975, p 197.
6.Chabner, B. A.; Allegra, C. J.; Curt, G. A.; Calabresi, P. In Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 9th ed.; Hardman, J. G., Limbird, L. E., Molinoff, P. B., Ruddon, R. W., Gilman, A. G., Eds.; McGraw-Hill: New York, 1996, p 1233.
7.Goldberg, I. H.; Friedman, P. A. Annu. ReV. Biochem. 1971, 40, 775.
8.Waring, M. J. Annu. ReV. Biochem. 1981, 50, 159.
9.Van Dyke, M. W.; Dervan, P. B. Biochemistry 1983, 22; 2373.
10.Stankus, A.; Goodisman, J.; Dabrowiak, J. C. Biochemistry 1992, 31; 9310.
11.Pereira, M. A.; Figueiredo de T. L.; Demicheli, C.; Spectrophotometric Study of Mithramycin Complexes With Cu(II), Fe(III), And Tb(III); Analytical Letters, 1997, 30, 2555-2563.
12.Kiang, D. T.; Loken, M. K.; Kennedy, B. J.; J. Chin. Endocrinol. Metab., 1979, 48, 341.
13.Ward, D. C.;Reich, E.;Goldberg, I. H.; Science, 1965, 149, 1259.
14.Aich, P.; Sen, R.; Dasgupta, D. Biochemistry, 1992, 31, 2988.
15.Aich, P.; Dasgupta, D. Biochemistry, 1995, 34, 1376.
16.Chakrabarti, S.; Mir, M. A.; Dasgupta, D. Biopolymers, 2001, 62, 131.
17.Banville, D. L.; Keniry, M. A.; Shafer, R. H. Biochemistry 1990, 29, 6521.
18.Xiaolian Gao, Dinshaw J. Patel. Biochemistry, 1990, 29, 10940.
19.Gao, X.; Patel, D. J. Biochemistry, 1989, 28, 751.
20.Aich, P.; Dasgupta, D. Biochem. Biophys. Res. Commun., 1990, 173, 689.
21.Aich, P.; Sen, R.; Dasgupta D. Chem.-Biol. Interact. 1992, 83, 23.
22.Fox, K. R.; Howarth, N. R. Nucleic Acids Res., 1985, 13, 8695.
23.Sastry, M.; Patel, D. J. Biochemistry, 1993, 32, 6588.
24.Andrews, D. W. Phys. Rev., 1930, 36, 544.
25.Verlet, L. Computer experiments on the Classical Fluids. I. Thermodynamical Properties of Lennard – Jones Molecules. Phys Rev. 1967, 159, 98.
26.Frank Jensen, Introduction to Computational Chemistry, JOHN WILEY & SONS, 1999, p.377.
27.Schlick, T., Rev. Comput. Chem., 1992, 3.; Schlegel, H. B., Adv. Chem. Phys., 1987, 67, 249.; Schlegel, H. B., Modern Electronic Structure Theory, PartI, ed.; Yarkony, D. World Scientific, 1995, 459-500.; Fletcher, R., Practical Methods of Optimizations, Wiley, 1980; McKee, M. L. and Page, M. Rev. Comput. Chem., 1993, 4, 35.
28.S. J. Weiner, P. A. Kollman, D. A. Case, U. C. Singh, C. Ghio, G. Alagona, S. Profeta Jr., and P. Weiner,; A New Force Field for Molecular Mechanical Simulation of Nucleic Acids and Protein, J. Am. Chem. Soc., 1984, 106, 765.
29.S. J. Weiner, P. A. Kollman, D. T. Nguyen, and D. A. Case,; An All Atom Force Field for Simulations of Proteins and Nucleic Acids. J. Comput. Chem., 1986, 7, 230.
30.B. R. Brooks, R. E. Bruccoleri, B. D. Olafson, D. J. States,; A Program for Macromolecular Energy, Minimization, and Dynamics Calculations. J. Comput. Chem., 1983, 4, 187.
31.W. F. van Gunsteren, H. J. C. Berendsen, J. Hermans, W. G. J. Hol, and J. P. M. Postma,; Computer Simulation of the Dynamics of Hydrated Protein Crystals and Its Comparison with X-Ray Data. Proc. Natl. Acad. Sci. U.S.A., 1983, 80, 4315.
32.J. Åqvist, W. F. van Gunsteren, M. Leijonmark, and O. Tapia, A Molecular Study of the C-Terminal Fragment of the L7/L12 Ribosomal Protein. Secondary Structure Motion in a 150 Picosecond Trajectory. J. Mol. Biol., 1985, 183, 461.
33.Todd, J. A. Ewing, Shingo Makinoa, A. Geoffrey Skillmana and Irwin D. Kuntza, Journal of Computer-Aided Molecular Design, 2001, 15, 411-428.
34.Gaussian 98 (Revision A.11), M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria, M. A. Robb, J. R. Cheeseman, V. G. Zakrzewski, J. A. Montgomery, R. E. Stratmann, J. C. Burant, S. Dapprich, J. M. Millam, A. D. Daniels, K. N. Kudin, M. C. Strain, O. Farkas, J. Tomasi, V. Barone, M. Cossi, R. Cammi, B. Mennucci, C. Pomelli, C. Adamo, S. Clifford, J. Ochterski, G. A. Petersson, P. Y. Ayala, Q. Cui, K. Morokuma, D. K. Malick, A. D. Rabuck, K. Raghavachari, J. B. Foresman, J. Cioslowski, J. V. Ortiz, B. B. Stefanov, G. Liu, A. Liashenko, P. Piskorz, I. Komaromi, R. Gomperts, R. L. Martin, D. J. Fox, , T. Keith, M. A. Al-Laham, C. Y. Peng, A. Nanayakkara, C. Gonzalez, M. Challacombe, P. M. W. Gill, B. G. Johnson, W. Chen, M. W. Wong, J. L. Andres, M. Head-Gordon, E. S. Replogle, and J. A. Pople, Gaussian, Inc., Pittsburgh, PA, 1998.
35.J. Tomasi, Quantum Theory of Chemical Reactions, R. Daudel, A. Pullman, L. Salem, and A. Veillard, Eds., Reidel, Dordrecht, On the Use of Electrostatic Molecular Potentials in Theoretical Investigations on Chemical Reactivity. 1980, Vol1, 191-228
36.P. Politzer and D. G. Truhlar, Eds., Chemical Applications of Atomic and Molecular Electrostatic Potentials, Plenum Press, New York, 1981
37.Allen, F.H. et al. J. Chem. Soc. Perkins Trans. 1987 II. s1.
38.Bayly, C. I., P. et al. J. Phys. Chem. 1993, 97, 10269.
39.Cornell, W. D. et al. J. Am. Chem. Soc. 1995, 115, 9620.
40.Lifson, & Warshel, J. Phys. Chem. 1968, 49, 5116.
41.MacKerrel et al. J. Am. Chem. Soc. 1995, 117, 11946.
42.Weiner et al. J. Am. Chem. Soc. 1983, 106, 765.
43.SYBYL Molecular Modeling System (Version 6.8) from Tripos Associates Inc.
44.WebLab Viewer(Version 3.7) from MSI Accelrys Inc.
45.Guex, N. and Peitsch, M.C.; SWISS-MODEL and the Swiss-PdbViewer: An environment for comparative protein modeling. Electrophoresis, 1997, 18, 2714-2723.
46.W. L. Jorgensen, J. Chandrasekhar, J. F. Madura, R. W. Impey, and M. L. Klein,; Comparison of Simple Potential Functions for Simulating Liquid Water. J. Phys. Chem., 1983, 79, 926.
47.Pathiaseril A, Woods, R. J.; Relative energies of binding for antibody-carbohydrate-antigen complexes computed from free-energy simulations.; J. Am. Chem. Soc., 2000, 122, 331.
48.AMBER7 User’s Manual, Appendix C.
49.T.E. Cheatham, III, P. Cieplak & P.A. Kollman. A modified version of the Cornell et al. force field with improved sugar pucker phases and helical repeat. J. Biomol. Struct. Dyn., 1999, 16, 845-862.
50.Junmei Wang, Piotr Cieplak, Peter A. Kollman, J. Comput. Chem. 2000, 21, 1049-1074.
51.C.I. Bayly, P. Cieplak, W.D. Cornell, and P.A. Kollman,; A Well-Behaved Electrostatic Potential Based Method Using Charge Restraints For Determining Atom-Centered Charges: The RESP Model,; J. Phys. Chem., 1993, 97, 10269.
52.AMBER7 User’s Manual, Appendix D.
53.Howard, A.E., Cieplak, P., and Kollman, P.A.; A Molecular Mechanical Model that Reproduces the Relative Energies for Chair and Twist-Boat Conformations of 1,3-Dioxanes, J. Comp. Chem., 1995, 16:2, 243-261.
54.Thomas E. Cheatham, III, Matthew, A. Young, Biopolymers (Nucleic Acid Sciences), 2001, 56, 232–256
55.T. Darden, D. York, and L. Pederson, J. Chem. Phys., 1993, 98, 10089.
56.J. P. Ryckaert, G. Ciccotti, and H. J. C. Berendsen,; Numerical Integration of the Cartesian Equations of Motion of a System with Constraints: Molecular Dynamics of n-Alkanes. J. Comput. Phys., 1977, 23, 237.
57.Shields, G. C.; Laughton, C. A.; Orozco, M. J. Am. Chem. Soc. 1997, 119, 7463-7469.
58.H.J.C. Berendsen, J.P.M. Postma, W.F. van Gunsteren, A. DiNola & J.R. Haak.; Molecular dynamics with coupling to an external bath. J. Chem. Phys., 1984, 81, 3684-3690.
59.Sarah A. Harris, Evripidis Gavathiotis, Mark S. Searle, Modesto Orozco, Charles A. Laughton; Cooperativity in Drug – DNA Recognition: A Molecular Dynamics Study. J. Am. Chem. Soc. 2001, 123, 12658-12663.
60.V. Tsui & D.A. Case. Theory and applications of the generalized Born solvation model in macromolecular simulations. Biopolymers (Nucl. Acid. Sci.) 56, 275-291 (2001).
61. M.L. Connolly. Analytical molecular surface calculation. J. Appl. Cryst. 16, 548-558 (1983).
62. Lavery, R.; Sklenar, H. J. Biomol. Struct. Dyn. 1989, 6, 63-91.