Conformational Flexibility of the DNA Backbone

Schuerman, Geertrui; Meervelt, Luc Van

doi:10.1021/ja992180m

Cited by 20 publications

(15 citation statements)

References 21 publications

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“…Determination of DNA–anthracycline hydration patterns utilized sixteen complexes [Nucleic Acid Database (NDB) IDs: DD000,31, DDF001,1, DDF020,2, DDF022,32, DDF023,33, DDF026,34 DDF035,9 DDF041,35 DDF044,4 DDF045,4 DDF062,36 DDFB24,33 DDFB25,34 DDFB70,37 DDFP21,3 and the structure described here]. For evaluation of major groove ligand interactions, the purine ring atoms of G(2) of three bis‐intercalative complexes (NDB IDs: DD0018, DDD030, and DDDB46) was superimposed on G(2) of the current model.…”

Section: Methodsmentioning

confidence: 99%

Surprising roles of electrostatic interactions in DNA–ligand complexes

2003

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The positions of cations in x-ray structures are modulated by sequence, conformation, and ligand interactions. The goal here is to use x-ray diffraction to help resolve structural and thermodynamic roles of specifically localized cations in DNA-anthracycline complexes. We describe a 1.34 A resolution structure of a CGATCG(2)-adriamycin(2) complex obtained from crystals grown in the presence of thallium (I) ions. Tl(+) can substitute for biological monovalent cations, but is readily detected by distinctive x-ray scattering, obviating analysis of subtle differences in coordination geometry and x-ray scattering of water, sodium, potassium, and ammonium. Six localized Tl(+) sites are observable adjacent to each CGATCG(2)-adriamycin(2) complex. Each of these localized monovalent cations are found within the G-tract major groove of the intercalated DNA-drug complex. Adriamycin appears to be designed by nature to interact favorably with the electrostatic landscape of DNA, and to conserve the distribution of localized cationic charge. Localized inorganic cations in the major groove are conserved upon binding of adriamycin. In the minor groove, inorganic cations are substituted by a cationic functional group of adriamycin. This partitioning of cationic charge by adriamycin into the major groove of CG base pairs and the minor groove of AT base pairs may be a general feature of sequence-specific DNA-small molecule interactions and a potentially useful important factor in ligand design.

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Section: Methodsmentioning

confidence: 99%

Surprising roles of electrostatic interactions in DNA–ligand complexes

2003

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“…These authors have also obtained similar results for savinase at 0.9 A Ê resolution. Several structures have been reported (Jelsch et al, 1998(Jelsch et al, , 2000Schuerman & Van Meervelt, 2000;Ko et al, 2003;Howard et al, 2004) in which peaks in the middle of individual bonds (bond electrons) were seen for well ordered parts of the structure, indicating the deformation density. Our attempts to observe bond electrons for individual bonds in different macromolecular structures resulted in a partial success: these peaks were observed for some structures but not all.…”

Section: Introductionmentioning

confidence: 98%

On the possibility of the observation of valence electron density for individual bonds in proteins in conventional difference maps

Afonine

Lunin

Muzet

et al. 2004

Acta Crystallogr D Biol Crystallogr

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In the last decade, high-resolution data have become available for macromolecular objects. Furthermore, ultrahigh-resolution diffraction data (resolution close to 0.6 A) have been collected for several protein crystals. This allows the study of fine details of the electron-density distribution such as the deformation density, i.e. the deviation of the experimentally determined electron density from the density composed of 'free' non-bonded atoms. This paper discusses the resolution and atomic temperature factors necessary to make the valence electron density visible at individual bonds in conventional difference maps for macromolecules. The study of theoretical maps calculated by quantum-chemistry methods allows estimation of these conditions; these results are confirmed by analysis of experimental maps for Leu-enkephalin and antifreeze protein RD1. A resolution limit close to 0.6 A was found to be highly important for refinement even when the maps were calculated at lower resolution. The refinement of the same models at near to 0.9 A resolution results in artificially increased values of the atomic displacement parameters and does not permit bond electron density to be visible in difference maps. To some extent, overestimation of the atomic displacement parameters may be restricted if dummy bond electrons are used in the refinement.

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“…Although there is a wealth of studies that have investigated the DNA backbone, the question of interconversion times of the two B-DNA phosphate conformations, so far, have only been treated for single steps. [24][25][26][27][28][29][30][31][32][33][34][35] In the present study, we are looking at the interconversion from one state to the other, starting from a restrained system. For that purpose, we performed several 10-ns MD simulations of the EcoRI DNA dodecamer d(CGC-GAATTCGCG) 2 , with all phosphates forced into the B I or B II state by restraints.…”

Section: Introductionmentioning

confidence: 99%

Dynamics of DNA: B_Iand B_IIPhosphate Backbone Transitions

et al. 2004

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In the present study, we try to determine if the dynamics of the B-DNA backbone phosphates (and especially their interconversions between their two distinct conformations B I and B II ) are fast enough to be sufficiently sampled in the course of molecular dynamics simulations in the nanosecond time range. For this purpose, we performed twelve 10-ns simulations of the Drew-Dickerson dodecamer d(CGCGAATTCGCG) 2 to investigate the dynamics of B I /B II interconversion. We forced the DNA backbone angles and with restraints to values that are characteristic for B I and B II , resulting in DNA double helices with all phosphates in the B I or B II substate. These restraints were removed after 10 ns, and unrestrained simulations at temperatures of 250, 275, 287.5, 300, and 325 K were performed for another 10 ns, which allowed us to analyze the dynamics of relaxation in detail. These simulations were compared to simulations of the undisturbed dodecamer at 250 and 300 K, as a reference for the equilibrated state. We found that the relaxation from the B II state is considerably fast, with high rate constants, and is dependent on temperature. From this temperature dependence of the rate constants, we calculated the activation energy necessary for the B II to B I transition to be 2.5 kcal/mol. Half-life times of the B II state derived from the relaxation process are in the range of 110-370 ps, which indicates that a simulation time of 10 ns is sufficiently long to investigate conformational transitions of the DNA backbone. The structures of the all-B I DNA are more similar to structures found for the DrewDickerson dodecamer by X-ray crystallography than the all-B II DNA. This fact is not astonishing, because the B I conformation has been observed to be privileged. Nevertheless, both structures are quite different from canonical A-or B-DNA. That observation is revealing, because we expected the all-B II DNA to be the transition state to canonical A-DNA or at least structurally very similar. Furthermore, we find that the relaxation of our rather-distorted starting structures is fast and, despite the large difference at the beginning, leads to a similar equilibrium, which, again, is similar to the undisturbed simulation.

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Conformational Flexibility of the DNA Backbone

Cited by 20 publications

References 21 publications

Surprising roles of electrostatic interactions in DNA–ligand complexes

Surprising roles of electrostatic interactions in DNA–ligand complexes

On the possibility of the observation of valence electron density for individual bonds in proteins in conventional difference maps

Dynamics of DNA: B_Iand B_IIPhosphate Backbone Transitions

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Conformational Flexibility of the DNA Backbone

Cited by 20 publications

References 21 publications

Surprising roles of electrostatic interactions in DNA–ligand complexes

Surprising roles of electrostatic interactions in DNA–ligand complexes

On the possibility of the observation of valence electron density for individual bonds in proteins in conventional difference maps

Dynamics of DNA: BIand BIIPhosphate Backbone Transitions

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Dynamics of DNA: B_Iand B_IIPhosphate Backbone Transitions