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研究生:陳仕元
研究生(外文):Chen, Shih-Yuan
論文名稱:分子動力模擬與結合自由能計算研究抗生素與寡核酸間的辨識與作用:(I)Mithramycin與DNA(II)胺基糖苷型抗生素與核糖體RNA的A-site
論文名稱(外文):Molecular Dynamics Study and Binding Free Energy Calculation on Recognition and Interaction Between Antibiotics and Oligonucleotides: (I) Mithramycin and DNA (II) Aminoglycosides and Ribosomal RNA A-Site
指導教授:林志侯
指導教授(外文):Lin, Thy-Hou
學位類別:博士
校院名稱:國立清華大學
系所名稱:分子醫學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2009
畢業學年度:98
語文別:英文
論文頁數:99
中文關鍵詞:結合辨識分子動力結合自由能構形熵胺基糖苷型抗生素核糖體RNA A位點
外文關鍵詞:binding recognitionmolecular dynamicsbinding free energyconformational entropyhydration patternaminoglycosidemithramycinrRNA A-site
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分子動力模擬允許對原子層級的結構動力現象進行細節分析,例如生物領域中十分重要的分子間結合與辨識。參與(生物)分子間的結合作用力則可藉由基於熱力學定律的結合自由能計算做為評估。對於分子動態特性要點的構形柔軟度則可藉由計算構形熵,例如主成份分析的方法來估計。綜合這些方法,可對於僅止於靜態結構模型上難以說明的原子層級現象,提供合理的解釋。在這一篇我們呈現了一系列的典型分子動力模擬的結果,用於探討介於 (I) mithramycin二聚物與一段雙股DNA, (II) 數個胺基糖苷型抗生素與對應核糖體RNA A-site之寡核酸之間的結合辨識與作用力。這兩種抗生素都是由一個主要結構做為核心,並且於此處不同的碳原子位置衍生出數個糖環取代基所形成的。在第一部份(I)的研究,我們成功地建立了與實驗(核磁共振)結構及實驗結合親和力一致的動力模型,對結合作用力進行討論,並且發現此一對於DNA GC鹼基有專一結合性的抗生素對於具有兩個GC鹼基結合部位的雙股DNA(由十對核苷酸組成)之間是反協同性的結合。採用此一分子動力模擬的方法以及對這樣糖基連結的抗生素所修改的分子力場參數,在第二部分(II)的研究裡,我們對於數種胺基糖苷型抗生素以及一段能代表A-site的雙股RNA (A-site位於30S次單元上的16S核糖體RNA,30S對於細菌進行RNA轉譯形成蛋白質是相當重要的場所)之間的結合辨識及形成的水分子佔據型態進行比較。我們建立了數個具有合理的結合自由能的動態分子模型,並且與實驗數據間呈現良好的線性相關。分析在A-site上的U1406·U1495鹼基對周圍的水分子佔據部位,並區別出快速交換或者是與結合部位緊密結合的水分子。這樣的水分子佔據時間的分析在先前的研究中被提出對於循理性藥物設計是有幫助的。我們發現了在4,6-雙取代型抗生素 (tobramycin與kanamycin A) 的第三個糖環與G1405/U1406鹼基的磷酸基團上的氧原子間具有長時間的水分子佔據部位,這可能值得進一步探討作為這一類抗生素的循理性設計。
Molecular dynamics (MD) simulations allow detail analysis of structural dynamics of atomic–level phenomena such as binding recognition fundamental in Biology field. Binding interaction involved between (bio) –molecules can be evaluated by binding free energy calculation base on the law of thermodynamics. Conformational flexibility essential for investigating dynamic property can be estimated by calculating conformational entropy such as principal components analysis. Combination with these techniques can provide reasonable explanations for atomic–level phenomena that are difficult to explain on the basis of static models alone. Here we present the results of a series of conventional MD simulations on recognition and interaction between (I) a mithramycin dimer and a DNA duplex, (II) several aminoglycoside antibiotics and an oligonucleotide corresponding to rRNA A–site. Both kinds of antibiotics consist of a core structure where several sugar ring substitutions at different carbon positions. In part I of the study, we successfully built the dynamics model corresponding to the experimental structure and binding affinity, discussed the binding interaction, and found the cooperativity between this GC–specific DNA binding antibiotic and a decanucleotide duplex of two GC binding sites to be in an anticooperative manner. Following the MD protocol and modification of the force field parameters for this sugar–linked antibiotic, in part II of the study, we compared the binding recognition and hydration patterns between several aminoglycoside antibiotics and a RNA duplex corresponding to the aminoacyl–tRNA decoding site (A–site) of the 16S rRNA on the 30S subunit which is a crucial component of the bacterial translational machinery. We have built several dynamic models with reasonable binding free energies showing good linear correlation with the experimental data. The hydration sites around the U1406·U1495 pair in the A–site were analyzed to distinguish tightly bound water molecules from fast–exchanging ones which has been suggested to be useful for rational drug design. We found that the hydration sites with long residence time identified between ring III of two 4,6–disubstituted antibiotics (tobramycin and kanamycin A) and phosphate oxygen atoms of G1405/U1406 may be worthy of further exploration for rational design of this kind.
Chapter 1 Introduction -------------------------------------------------------- 6
1.1 General information --------------------------------------------------------------------------------- 7
1.2 Research background of (I) mithramycin dimer and DNA duplex ---------------------------- 10
1.3 Research background of (II) aminoglycoside antibiotics and rRNA A–site ----------------- 13
1.4 Incentive and aims ----------------------------------------------------------------------------------- 17
1.5 Figures and tables ----------------------------------------------------------------------------------- 20

Chapter 2 Materials and Methods ---------------------------------------------------------------------- 24
2.1 General introduction of conventional MD simulations ----------------------------------------- 25
2.2 Materials & modeling ------------------------------------------------------------------------------- 28
2.3 Methods: MD simulations -------------------------------------------------------------------------- 31
2.4 Methods: Binding free energy & conformational entropy calculation ----------------------- 32
2.5 Methods: Essential dynamics & PCA (principal component analysis) ----------------------- 35
2.6 Methods: Hydration analysis ----------------------------------------------------------------------- 37
2.7 Figures and tables ----------------------------------------------------------------------------------- 39

Chapter 3 Results and Discussion: (I) Mithramycin dimer and DNA duplex ----------------- 40
3.1 General inspection of MD simulations ------------------------------------------------------------ 41
3.2 Thermodynamic characterization of the binding event ----------------------------------------- 44
3.3 Cooperativity characterization: Entropic dissection and PCA analysis ----------------------- 46
3.4 Conclusion -------------------------------------------------------------------------------------------- 48
3.5 Figures and tables ----------------------------------------------------------------------------------- 49

Chapter 4 Results and Discussion: (II) Aminoglycoside antibiotics and rRNA A–site ------- 60
4.1 General inspection of MD simulations ------------------------------------------------------------ 61
4.2 Thermodynamic and essential dynamics characterization of binding affinities and
_____antibacterial activities ------------------------------------------------------------------------------- 63
4.3 Hydration sites and binding recognition ---------------------------------------------------------- 67
4.4 Conclusion -------------------------------------------------------------------------------------------- 74
4.5 Figures and tables ----------------------------------------------------------------------------------- 75

Chapter 5 Conclusion ------------------------------------------------------------------------------------- 90

Reference ---------------------------------------------------------------------------------------------------- 92

Appendix I. Publication list ------------------------------------------------------------------------------- 98
Appendix II. Abbreviation list ---------------------------------------------------------------------------- 99
1.Verlet, L. Computer "Experiments" on Classical Fluids. I. Thermodynamical Properties of Lennard-Jones Molecules. Phys. Rev., (1967) 159, 98–103.
2.Van Holde, K. E., W. C. Johnson, and P. S. Ho. Principles of Physical Biochemistry, Upper Saddle River, (1999) NJ: Prentice Hall.
3.Yarbo, J. W., Kennedy, B. J., Barnum, C. P. Mithramycin inhibition of ribonucleic acid synthesis. Cancer Res. (1968) 26, 36.
4.Miller, D. M., Polansky, D. A., Thomas, S. D., Ray, R., Campbell, V. W., Sanchez, J., Koller, C. A. Mithramycin selectively inhibits transcription of G-C containing DNA. Am. J. Med. Sci. (1987) 294, 388–394.
5.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.
6.Aich, P., Dasgupta, D. Role of Mg++ in the mithramycin-DNA interaction: Evidence for two types of mithramycin-Mg++ complex. Biochem. Biophys. Res. Commun. (1990) 173, 689–692.
7.Aich, P., Sen, R., Dasgupta D. Interaction between antitumor antibiotic chromomycin A3 and Mg2+. I. Evidence for the formation of two types of chromomycin A3-Mg2+ complexes. Chem.-Biol. Interact. (1992) 83, 23–33.
8.Aich, P., Sen, R., Dasgupta, D. Role of magnesium ion in the interaction between chromomycin A3 and DNA: binding of chromomycin A3-Mg2+ complexes with DNA. Biochemistry (1992) 31, 2988–2997.
9.Aich, P., Dasgupta, D. Role of magnesium ion in mithramycin-DNA interaction: binding of mithramycin-Mg2+ complexes with DNA. Biochemistry (1995) 34, 1376–1385.
10. Chakrabarti, S., Mir, M. A., Dasgupta, D. Differential interactions of antitumor antibiotics chromomycin A(3) and mithramycin with d(TATGCATA)(2) in presence of Mg(2+). Biopolymers (2001) 62, 131–140.
11. Banville, D. L., Keniry, M. A., Shafer, R. H. NMR studies of the interaction of chromomycin A3 with small DNA duplexes. Binding to GC-containing sequences. Biochemistry (1990) 29, 6521–6534.
12. Banville, D. L., Keniry, M. A., Shafer, R. H. NMR investigation of mithramycin A binding to d(ATGCAT)2: a comparative study with chromomycin A3. Biochemistry (1990) 29, 9294–9304.
13. Gao, X., Patel, D. J. Solution structure of the chromomycin-DNA complex. Biochemistry (1989) 28, 751–762.
14. Sastry, M., Patel, D. J. Solution structure of the mithramycin dimer-DNA complex. Biochemistry (1993) 32, 6588–6604.
15. Majee, S., Sen, R., Guha, S., Bhattacharyya, D., Dasgupta, D. Differential interactions of the Mg2+ complexes of chromomycin A3 and mithramycin with poly(dG-dC) x poly(dC-dG) and poly(dG) x poly(dC). Biochemistry (1997) 36, 2291–2299.
16. Gao, X., Patel, D. J. Chromomycin dimer-DNA oligomer complexes. Sequence selectivity and divalent cation specificity. Biochemistry (1990) 29, 10940–10956.
17. 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.
18.Chambers HF. In B. G. Katzung (ed.), Basic and clinical pharmacology, 9th ed. McGraw–Hill, (2004) New York, 764–772.
19.Fourmy D, Recht MI, Blanchard SC, Puglisi JD. Structure of the A site of Escherichia coli 16S ribosomal RNA complexed with an aminoglycoside antibiotic. Science (1996) 274, 1367–1371.
20.Fourmy D, Yoshizawa S, Puglisi JD. Paromomycin binding induces a local conformational change in the A–site of 16 s rRNA. J. Mol. Biol. (1998) 277, 333–345.
21.Yoshizawa S, Fourmy D, Puglisi JD. Structural origins of gentamicin antibiotic action. EMBO J. (1998) 17, 6437–6448.
22.Carter AP, Clemons WM, Brodersen DE, Morgan–Warren RJ, Wimberly BT, Ramakrishnan V. Functional insights from the structure of the 30S ribosomal subunit and its interactions with antibiotics. Nature (2000) 407, 340–348.
23.Vicens Q, Westhof E. Crystal structure of paromomycin docked into the eubacterial ribosomal decoding A site. Structure (2001) 9, 647–658.
24.Vicens Q, Westhof E. Crystal structure of geneticin bound to a bacterial 16 S ribosomal RNA A site oligonucleotide. J. Mol. Bio. (2003) 326, 1175–1188.
25.Fran�帙is B, Russell RJ, Murray JB, Aboul–ela F, Masquida B, Vicens Q, Westhof E. Crystal structures of complexes between aminoglycosides and decoding A site oligonucleotides: role of the number of rings and positive charges in the specific binding leading to miscoding. Nucleic Acid Res. (2005) 33, 5677–5690.
26.Vicens Q, Westhof E. Crystal structure of a complex between the aminoglycoside tobramycin and an oligonucleotide containing the ribosomal decoding A site. Chem. Biol. (2002) 9, 747–755.
27.Kaul M, Pilch DS. Thermodynamics of aminoglycoside–rRNA recognition: The binding of neomycin–Class aminoglycosides to the A site of 16S rRNA. Biochemistry (2002) 41, 7695–7706.
28.Pilch DS, Kaul M, Barbieri CM, Kerrigan JE. Thermodynamics of aminoglycoside–rRNA recognition. Biopolymers (2003) 70, 58–79.
29.Yang G, Trylska J, Tor Y, McCammon JA. Binding of aminoglycosidic antibiotics to the oligonucleotide A–site model and 30S ribosomal subunit: Poisson–Boltzmann model, thermal denaturation, and fluorescence studies. J. Med. Chem. (2006) 49, 5478–5490.
30.Kaul M, Barbieri CM, Kerrigan JE, Pilch DS. Coupling of drug protonation to the specific binding of aminoglycosides to the A site of 16 S rRNA: elucidation of the number of drug amino groups involved and their identities. J. Mol. Biol. (2003) 326, 1373–1387.
31.Yoshizawa S, Fourmy D, Puglisi JD. Recognition of the codon–anticodon helix by ribosomal RNA. Science (1999) 285, 1722–1725.
32.Kaul M, Barbieri CM, Pilch DS. Aminoglycoside–induced reduction in nucleotide mobility at the ribosomal RNA A–site as a potentially key determinant of antibacterial activity. J. Am. Chem. Soc. (2006) 128, 1261–1271.
33.Sanbonmatsu KY. Energy landscape of the ribosomal decoding center. Biochimie (2006) 88, 1053–1059.
34.Vaiana AC, Sanbonmatsu KY. Stochastic Gating and Drug–Ribosome Interactions. J. Mol. Biol. (2009) 386, 648–661.
35.Meroueh SO, Mobashery S. Conformational transition in the aminoacyl t–RNA site of the bacterial ribosome both in the presence and absence of an aminoglycoside antibiotic. Chem. Biol. Drug. Des. (2007) 69, 291–297.
36.Vaiana AC, Westhof E, Auffinger P. A molecular dynamics simulation study of an aminoglycoside/A–site RNA complex: conformational and hydration patterns. Biochimie. (2006) 88, 1061–1073.
37.Romanowska J, Setny P, Trylska J. Molecular dynamics study of the ribosomal A–site. J. Phys. Chem. B (2008) 112, 15227–15243.
38.Berveridge, D. L., McConnell, K. J. Nucleic acids: theory and computer simulation, Y2K. Curr. Opin. Struct. Biol. (2000) 10, 182.
39.Cheatham, T. E., III, Kollman, P. A. Molecular dynamics simulation of nucleic acids. Annu. ReV. Phys. Chem. (2000) 51, 435.
40.Auffinger, P. & Vaiana, A. C. Molecular dynamics simulations of RNA systems. In Handbook of RNA biochemistry (Westhof, Bindereif, Schon & Hartmann, eds.) (2005) 560–576. Willey-VCH, Manheim.
41.Durante-Mangoni E, Grammatikos A, Utili R, Falagas ME. Do we still need the aminoglycosides? Int J Antimicrob Agents. (2009) 33, 201–205.
42.Wang J, Cieplak P, Kollman PA. How well does a restrained electrostatic potential (resp) model perform in calculating conformational energies of organic and biological molecules. J. Comput. Chem. (2000) 21, 1049–1074.
43.Jorgensen WL, Chandrasekhar J, Madura J, Impley RW, Klein ML. Comparison of simple potential functions for simulating liquid water. J. Chem. Phys. (1983) 79, 926–935.
44.Bayly CI, Cieplak P, Cornell WD, Kollman PA. A well–behaved electrostatic potential based method using charge restraints for determining atom–centered charges: the RESP model. J. Phys. Chem. (1993) 97, 10269–10280.
45.Pathiaseril A, Woods RJ. Relative energies of binding for antibody–carbohydrate–antigen complexes computed from free–energy simulations. J. Am. Chem. Soc. (2000) 122, 331–338.
46.Recht MI, Fourmy D, Blanchard SC, Dahlquist KD, Puglisi JD. RNA sequence determinants for aminoglycoside binding to an A–site rRNA model oligonucleotide. J. Mol. Biol. (1996) 262, 421–436.
47.Case DA, Darden TA, Cheatham ITE, Simmerling CL, Wang J, Duke RE, Luo R, Merz KM, Wang B, Pearlman DA, Crowley M, Brozell S, Tsui V, Gohlke H, Mongan J, Hornak B, Cui G, Beroza P, Scafmeister C, Caldwell JW, Ross WS, Kollman PA. AMBER8. (2004) San Francisco: University of California.
48.Darden, T., York, D., Pedersen, L. Particle mesh Ewald: an N log(N) method for Ewald sums in large systems. J. Chem. Phys. (1993) 98, 10089–10092.
49.Ryckaert, J. P., Ciccotti, G., Berendsen, H. J. C. Numerical integration of the Cartesian equations of motion of a system with constraints; molecular dynamics of n–alkanes. J. Comput. Phys. (1977) 23, 237.
50.Tsui V, Case DA. Theory and applications of the generalized Born solvation model in macromolecular simulations. Biopolymers (2001) 56, 275–291.
51.McQuarrie DA. Statistical mechanics. (1976) New York: Harper and Row.
52.Schlitter J. Estimation of absolute and relative entropies of macromolecules using the covariance matrix. Chem. Phys. Lett. (1993) 215, 617–621.
53.Kitao A, Go N. Investigating protein dynamics in collective coordinate space. Curr. Opin. Struct. Biol. (1999) 9, 164–169.
54.Berendsen HJ, Hayward S. Collective protein dynamics in relation to function. Curr. Opin. Struct. Biol. (2000) 10, 165–169.
55.Amadei A, Linssen AB, Berendsen HJ. Essential dynamics of proteins. Proteins (1993) 17, 412–425.
56.Lavery R, Sklenar H. The definition of generalized helicoidal parameters and of axis curvature for irregular nucleic acids. J. Biomol. Struct. Dyn. (1988) 6, 63–91.
57.Berendsen HJ, Van der Spoel D, Van Drunen R. GROMACS: A message–passing parallel molecular dynamics implementation. Comp. Phys. Comm. (1995) 91, 43–56.
58.Ceruso MA, Amadei A, Di Nola A. Mechanics and dynamics of B1 domain of protein G: role of packing and surface hydrophobic residues. Protein. Sci. (1999) 8, 147–160.
59.van Aalten DM, Conn DA, de Groot BL, Berendsen HJ, Findlay JB, Amadei A. Protein dynamics derived from clusters of crystal structures. Biophys. J. (1997) 73, 2891–2896.
60.de Groot BL, Hayward S, van Aalten DM, Amadei A, Berendsen HJ. Domain motions in bacteriophage T4 lysozyme: a comparison between molecular dynamics and crystallographic data. Proteins (1998) 31, 116–127.
61.Sorin E.J., Rhee Y.M., Pande V.S. Does water play a structural role in the folding of small nucleic acids? Biophys. J. (2005) 88, 2516–2524.
62.Simone De A., Dodson G.G., Verma C.S., ZagariA., Fraternali F. Prion and water: tight and dynamical hydration sites have a key role in structural stability. Proc. Natl. Acad. Sci. USA (2005) 102, 7535–7540.
63.Rhodes M.M, R�繅lov�� K, Sponer J, Walter N.G. Trapped water molecules are essential to structural dynamics and function of a ribozyme. Proc. Natl. Acad. Sci. USA (2006) 103, 13380–13385.
64.Papoian G.A., Ulander J., Eastwood M.P., Luthey-Schulten Z., Wolynes P.G. Water in protein structure prediction. Proc. Natl. Acad. Sci. USA (2004) 101, 3352–3357.
65.Petrone P.M., Garcia A.E. MHC-peptide binding is assisted by bound water molecules. J. Mol. Biol. (2004) 338, 419–435.
66.Verdonk M.L., ChessariG., Cole J.C., Hartshorn M.J., Murray C.W., Nissink J.W., Taylor R.D., Taylor R. Modeling water molecules in protein–ligand docking using GOLD. J. Med. Chem. (2005) 48, 6504–6515.
67.Henchman R.H., McCammon J.A. Extracting hydration sites around proteins from explicit water simulations. J. Comput. Chem. (2002) 23, 861–869.
68.Harris S. A., Gavathiotis E., Searle M. S., Orozco M., Laughton, C. A. Cooperativity in drug-DNA recognition: a molecular dynamics study. J. Am. Chem. Soc. (2001) 123, 12658–12663.
69.Schaefer M, Froemmel C. A precise analytical method for calculating the electrostatic energy of macromolecules in aqueous solution. J. Mol. Biol. (1990) 216, 1045–1066.
70.Schaefer M, Karplus M. A comprehensive analytical treatment of continuum electrostatics. J. Phys. Chem. (1996) 100, 1578–1599.
71.Bashford D, Case DA. Generalized born models of macromolecular solvation effects. Annu. Rev. Phys. Chem. (2000) 51, 129–152.
72.Recht MI, Douthwaite S, Puglisi JD. Basis for prokaryotic specificity of action of aminoglycoside antibiotics. EMBO J. (1999) 18, 3133–3138.
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