Two charge density studies on macrolide antibiotics...
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Two charge density studies on macrolide antibiotics: erythromycin and roxithromycin J. Holstein 1,3 , B. Dittrich 3 , C. Paulmann 2,5 , W. Morgenroth 3,4,5 , P. Luger 1 1 Institut f ¨ ur Chemie / Kristallographie der Freien Universit ¨ at Berlin, Fabeckstr. 36a, D-14195 Berlin, Germany 2 Mineralogisch-Petrologisches Institut, Universit ¨ at Hamburg, Grindelallee 48, D-20146 Hamburg, Germany 3 Institut f ¨ ur Anorganische Chemie, Georg August Universit ¨ at, Tammannstr. 4, D-37077 G ¨ ottingen, Germany 4 Department of Chemistry, Aarhus University, Langelandsgade 140, 8000 Aarhus C, Denmark 5 c/o DESY/HASYLAB, Notkestr. 85, 22607 Hamburg, Germany Macrolide antibiotics are known to eliminate the protein synthesis in the bacterial ribosome by blocking the tunnel that channels the nascent peptides away form the peptidyl transferase center. [1] Due to this biological attribute the electronic properties of these compounds, especially of func- tional groups, which interact with nucleotids of the peptidyl transferase cavity are of interest. Two high resolution X-Ray experiments were executed: For roxithromycin 405336 Bragg reflections of have been collected at 100K (wavelength 0.56 ˚ A) at beamline F1 up to a resolution of 1,25 ˚ A −1 in sinθ/λ (d=0.40 ˚ A) and were merged to 39480 unique refections. At the D3-beamline 177822 reflections (23653 unique) of erythromycin have been collected at 9K (wavelenght 0.5166 ˚ A) up to a resolution of 0.91 ˚ A −1 in sinθ/λ (d=0.55 ˚ A). Their chemical structure is based on a 14-membered lactone cycle, substited by a desosamine and Figure 1: ORTEP [2] representation of the molecular structure (50% probability) of ery- thromycin Figure 2: Structure of roxithromycin a clandinose sugar. The newly discovered modification of erythromycin is disordered. The ADP‘s are much larger, than expected for a 9 K measurement (figure 1). Therefore no charge density analysis should be performed. The dataset of roxithromycin was refined with the program package XD [3] using the aspherical atom multipole formalism according to the method of Hansen and Coppens [4] . To obtain first results based on the invariant atom formalism [5] the progam INVARIOMTOOL [6] 1553
Transcript of Two charge density studies on macrolide antibiotics...
Two charge density studies on macrolideantibiotics: erythromycin and roxithromycin
J. Holstein1,3, B. Dittrich3, C. Paulmann2,5, W. Morgenroth3,4,5, P. Luger1
1Institut fur Chemie / Kristallographie der Freien Universitat Berlin, Fabeckstr. 36a, D-14195Berlin, Germany
2Mineralogisch-Petrologisches Institut, Universitat Hamburg, Grindelallee 48, D-20146 Hamburg,Germany
3Institut fur Anorganische Chemie, Georg August Universitat, Tammannstr. 4, D-37077 Gottingen,Germany
4Department of Chemistry, Aarhus University, Langelandsgade 140, 8000 Aarhus C, Denmark5c/o DESY/HASYLAB, Notkestr. 85, 22607 Hamburg, Germany
Macrolide antibiotics are known to eliminate the protein synthesis in the bacterial ribosome byblocking the tunnel that channels the nascent peptides away form the peptidyl transferase center.[1] Due to this biological attribute the electronic properties of these compounds, especially of func-tional groups, which interact with nucleotids of the peptidyl transferase cavity are of interest. Twohigh resolution X-Ray experiments were executed:For roxithromycin 405336 Bragg reflections of have been collected at 100K (wavelength 0.56 A)at beamline F1 up to a resolution of 1,25 A−1 in sinθ/λ (d=0.40 A) and were merged to 39480unique refections. At the D3-beamline 177822 reflections (23653 unique) of erythromycin havebeen collected at 9K (wavelenght 0.5166 A) up to a resolution of 0.91 A−1 in sinθ/λ (d=0.55 A).Their chemical structure is based on a 14-membered lactone cycle, substited by a desosamine and
Figure 1: ORTEP [2] representation of themolecular structure (50% probability) of ery-thromycin
Figure 2: Structure of roxithromycin
a clandinose sugar.The newly discovered modification of erythromycin is disordered. The ADP‘s are much larger,than expected for a 9 K measurement (figure 1). Therefore no charge density analysis should beperformed. The dataset of roxithromycin was refined with the program package XD [3] using theaspherical atom multipole formalism according to the method of Hansen and Coppens [4] .To obtain first results based on the invariant atom formalism [5] the progam INVARIOMTOOL [6]
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was used. The figures 3 and 4 were generated with the program Moliso [8]. They show the electro-static potential mapped on an isosurface of the electron density on a level of 0.5 e·A−3 and 0.0067e·A−3, calculated using the method of Su and Coppens [7]. Figure 3 shows an extended negativeregion (red) which is accumulated around the oxygen atoms. The region around the dimethylamingroup (figure 4) is positively charged.
Figure 3: electrostatic potential on an isosurfaceof the electron density on a level of 0.5 e·A−3
Figure 4: electrostatic potential on an isosurfaceof the electron density on a level of 0.0067 e·A−3
(van der Waals surface)
References
[1] F. Schlunzen, R. Zarivach, J. Harms, A. Bashan, A. Tocilj, R. Albrecht, A. Yonath, F.Franceschi, Nature, 2001, 413, 814-821
[2] M.N. Burnett, C.K. Johnson, ORTEP-III, Oak Ridge Thermal Ellipsoid Plotting Programfor Crystal Structure Illustrations, ORNL-6895, Oak Ridge National Laboratory, (1996).
[3] XD2006 - A computer program for multipole refinement, topological analysis of chargedensities and evaluation of intermolecular interaction energies from experimental or theo-retical structure factors. Volkov, A.; Macchi, P.; Farrugia, L. J.; Gatti, C.; Mallinson, P.;Richter, T.; Koritsanszky, T. (2006).
[4] N. K. Hansen, P. Coppens, Acta Cryst. A, 1978, 34, 909-921
[5] B. Dittrich, T. Koritsanszky, P. Luger, Angew. Chem, 2004, 116, 2773-2776
[6] C. B. Hubschle, B. Dittrich, INVARIOMTOOL, Ein Programm zur Erleichterung des In-variomtransfers, 2004, Freie Universitat Berlin
[7] Z. W. Su, P. Coppens, Acta Cryst. A, 1992, 48, 188-197
[8] C. B. Hubschle, MOLISO, A Program for Colour Mapped Isosurfaces,J. Appl. Crystallogr.,2006, 39, 901
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