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• W2085482854 abstract "A detailed picture of hydration and counterion location in the B-DNA duplex d(GCGAATTCG) is presented. Detailed data have been obtained by single crystal x-ray diffraction at atomic resolution (0.89 Å) in the presence of Mg2+. The latter is the highest resolution ever obtained for a B-DNA oligonucleotide. Minor groove hydration is compared with that found in the Na+ and Ca2+ crystal forms of the related dodecamer d(CGCGAATTCGCG). High resolution data (1.45 Å) of the Ca2+ form obtained in our laboratory are used for that purpose. The central GAATTC has a very stable hydration spine identical in all cases, independent of duplex length and crystallization conditions (counterions, space group). However, the organization of the water molecules (tertiary and quaternary layers) associated with the central spine vary in each case. A detailed picture of hydration and counterion location in the B-DNA duplex d(GCGAATTCG) is presented. Detailed data have been obtained by single crystal x-ray diffraction at atomic resolution (0.89 Å) in the presence of Mg2+. The latter is the highest resolution ever obtained for a B-DNA oligonucleotide. Minor groove hydration is compared with that found in the Na+ and Ca2+ crystal forms of the related dodecamer d(CGCGAATTCGCG). High resolution data (1.45 Å) of the Ca2+ form obtained in our laboratory are used for that purpose. The central GAATTC has a very stable hydration spine identical in all cases, independent of duplex length and crystallization conditions (counterions, space group). However, the organization of the water molecules (tertiary and quaternary layers) associated with the central spine vary in each case. 2-methyl-2,4-pentanediol primary water layer secondary water layer When the first dodecamer structure in the B-form was established, a “spine of hydration” was found in the minor groove (1Drew H.R. Dickerson R.E. J. Mol. Biol. 1981; 151: 536-556Crossref Scopus (810) Google Scholar). Recent high resolution data on the same dodecamer (2Shui X. McFail-Isom L. Hu G. Williams L. Biochemistry. 1998; 37: 8341-8355Crossref PubMed Scopus (442) Google Scholar, 3Shui X. Sines C. McFail-Isom L. VanDerveer D. Williams L. Biochemistry. 1998; 37: 16877-16887Crossref PubMed Scopus (205) Google Scholar, 4Tereshko V. Minasov G. Egli M. J. Am. Chem. Soc. 1999; 122: 470-471Crossref Scopus (167) Google Scholar, 5Tereshko V. Minasov G. Egli M. J. Am. Chem. Soc. 1999; 121: 3590-3595Crossref Scopus (205) Google Scholar) have shown that a series of water hexagons may build up on the spine of hydration. However, some of the water-water distances are too long to be considered hydrogen bonds, and they correspond rather to Van der Waals contacts. An additional result of the studies mentioned above is that either K+ (3Shui X. Sines C. McFail-Isom L. VanDerveer D. Williams L. Biochemistry. 1998; 37: 16877-16887Crossref PubMed Scopus (205) Google Scholar) or Rb+ (5Tereshko V. Minasov G. Egli M. J. Am. Chem. Soc. 1999; 121: 3590-3595Crossref Scopus (205) Google Scholar) may partially occupy the water sites. It has also been suggested (2Shui X. McFail-Isom L. Hu G. Williams L. Biochemistry. 1998; 37: 8341-8355Crossref PubMed Scopus (442) Google Scholar) that Na+may also occupy the water sites, but this suggestion has been challenged (4Tereshko V. Minasov G. Egli M. J. Am. Chem. Soc. 1999; 122: 470-471Crossref Scopus (167) Google Scholar, 6Neidle S. Nat. Struct. Biol. 1998; 9: 754-756Crossref Scopus (20) Google Scholar). The use of flash cooling and synchrotron radiation allows a much higher resolution in the x-ray diffraction data of oligonucleotides than was possible a few years ago. As a result, a much greater detail on water and ion distribution can be obtained. The detailed study of water and ions around DNA is interesting in itself, but it is also relevant to understand protein-DNA interactions. It has been suggested (7Otwinowski Z. Schevitz W. Zhang R.-G. Lawson C.L. Joachimiak A. Marmorstein R.Q. Luisi B.F. Sigler P.B. Nature. 1988; 335: 321-329Crossref PubMed Scopus (798) Google Scholar, 8Billeter M. Güntert P. Luginbühl P. Wüthrich K. Cell. 1996; 85: 1057-1065Abstract Full Text Full Text PDF PubMed Scopus (102) Google Scholar) that water-mediated polar contacts may contribute to the specificity of protein-DNA recognition. A better understanding of water structure around DNA is essential to ascertain the eventual role of ions and hydration waters in DNA interactions. The data obtained from high resolution oligonucleotide structures will be of great value in this sense. Here we report the arrangement of water and divalent cations in the related structures of d(GCGAATTCG) in the presence of Mg2+(resolution = 0.89 Å) and the calcium form of d(CGCGAATTCGCG) (resolution = 1.45 Å). The high resolution achieved with these structures allows us to position with certainty many of the water and ions in the crystal. Thus, the influence of either monovalent (Na+) or divalent (Mg2+, Ca2+) cations can be ascertained. The structure of the water spine is very clear and allows us to determine which water molecules occupy fixed positions. Hydrogen bonds and Van der Waals contacts can be clearly distinguished. The nonamer was crystallized, using a batch method, in sitting drops containing 0.5 mm DNA duplex, 1 mm acridine (Arg4) drug-peptide adduct, 20 mm sodium cacodylate buffer, pH 7, 100 mm MgCl2, and 35% MPD.1 Crystals grow in approximately 2 months to a typical size of 0.6 x 0.4 x 0.4 mm. The dodecamer crystallization is described elsewhere (9Liu J. Malinina L. Subirana J.A. FEBS Lett. 1998; 438: 211-214Crossref PubMed Scopus (24) Google Scholar, 10Liu J. Subirana J.A. J. Biol. Chem. 1999; (in press)Google Scholar). For data collection, crystals were mounted in a fiber loop and immediately flash-cooled at 120 K under a nitrogen vapor stream using an Oxford Cryosystems Cryostream. Data were collected using synchrotron radiation at EMBL beam line X11 in the DESY (Deutsches Elektronen-Synchrotron) Hamburg Outstation on a 345-mm MAR Research imaging-plate scanner. Three sets of data were collected at resolution cut-offs 0.89, 1.5, and 2.64 Å to avoid saturation of the high intensity reflections. The data were processed and reduced with DENZO and SCALEPACK software packages (11Otwinowski Z. Minor W. Methods Enzymol. 1997; 276: 307-326Crossref PubMed Scopus (38617) Google Scholar). The nonamer structure previously reported (12Vlieghe D. Van Meervelt L. Dautant A. Gallois B. Précigoux G. Kennard O. Acta Crystallogr. Sect. D. 1996; 52: 766-775Crossref PubMed Scopus (16) Google Scholar) at 2.05 Å resolution was used as a starting model. It was refined in XPLOR 3.8 (13Brünger A.T. X-PLOR Manual , version 3.851. Yale University Press, New Haven, CT1996Google Scholar) with a least-square target between 30 and 1.1 Å (Rfree = 0.248; Rfactor = 0.222). Simulated annealing protocols were employed. After running some cycles with XPLOR, we switched to SHELXL (14Sheldrick G.M. Schneider T.R. Methods Enzymol. 1997; 277: 319-343Crossref PubMed Scopus (1892) Google Scholar), where anisotropic refinement was carried out with some conjugate gradient cycles using the maximum resolution. The remaining structure was built into 2 Fo −Fc electron density maps generated with SHELXPRO. The refinement converged at Rfactor = 0.145 for all data between 30 and 0.89 Å (F > 4 ς). A very clear Cl− ion was found between two Mg2+ ions. Two poorly ordered sodium ions (Bfactors = 24.1 and 71.6 Å2) near phosphate groups were tentatively assigned on the basis of several short distances (<2.6 Å) to neighbor water molecules. They were located on the major groove in regions where the solvent is not well ordered. They are not shown in the figures. The drug-peptide complex used in the crystallization was not found in the crystal. We expect to decrease the Rfactor by modeling the disordered regions. 2M. Soler-López, L. Malinina, and J. A. Subirana, work in progress. To our surprise only 110 water molecules could be precisely located, compared with 86 that were found in the structure reported (12Vlieghe D. Van Meervelt L. Dautant A. Gallois B. Précigoux G. Kennard O. Acta Crystallogr. Sect. D. 1996; 52: 766-775Crossref PubMed Scopus (16) Google Scholar) at 2.05 Å. An additional 5 molecules had closely spaced (<0.5 Å) alternative positions. Many other sites with partial occupancy appear to be present. No molecule of the MPD used for crystallization could be located. It appears that most of the rather large spaces available for solvent molecules are in a poorly ordered glassy state. However, there are regions that have a highly ordered water network, probably influenced by the presence of Mg2+ ions. Refinement details for the high resolution structure of the dodecamer are reported elsewhere (10Liu J. Subirana J.A. J. Biol. Chem. 1999; (in press)Google Scholar). Crystal data and refinement statistics for both structures are listed in Table I. Stereo views are shown in Fig. 1. The hydration spine, counterions, and their associated waters are also shown in the figure. In the case of the dodecamer in the R3 space group, a detailed comparison with the standard P212121 structure (2Shui X. McFail-Isom L. Hu G. Williams L. Biochemistry. 1998; 37: 8341-8355Crossref PubMed Scopus (442) Google Scholar) is presented elsewhere (10Liu J. Subirana J.A. J. Biol. Chem. 1999; (in press)Google Scholar).Table ICrystallographic and refinement statisticsDodecamerNonamerSpace groupR3P 2121 21 a (Å)41.1221.93 b (Å)41.1236.52 c (Å)99.9152.73 α = β (°)90.0090.00 γ (°)120.0090.00Duplexes/asymmetric unit11Completeness99.2%97.6%Resolution range (Å)8–1.4530–0.89Unique reflections11,00532,684Rsym1-aRsym = ∑hklj‖Ihklj − 〈Ihklj〉‖/∑hklj〈Ihklj〉. (overall/last shell)0.053/0.3370.059/0.300Rfactor1-bRfactor = ∑∥Fo‖ − ‖Fc∥/∑‖Fo‖, where ‖Fo‖ and ‖Fc‖ are the observed and calculated structure factor amplitudes, respectively, with 10% of the reflections ommited.(R > 4 ς)0.2100.145Rfree1-cRfree was calculated using a random set containing 10% of observations that were ommited during refinement.(F > 4 ς)0.2470.148Rfactor (all reflections)0.2110.145No. DNA atoms1-dHydrogens are not included in the dodecamer.454583No. ions3.33 Ca2+5 Mg2+, 2 Na+, 1 Cl−No. water molecules144144No. alternative occupancy watersNone5No. partial occupancy watersNone29Average B-factor (Å2) (DNA/water)31.3/40.89.2/23.11-a Rsym = ∑hklj‖Ihklj − 〈Ihklj〉‖/∑hklj〈Ihklj〉.1-b Rfactor = ∑∥Fo‖ − ‖Fc∥/∑‖Fo‖, where ‖Fo‖ and ‖Fc‖ are the observed and calculated structure factor amplitudes, respectively, with 10% of the reflections ommited.1-c Rfree was calculated using a random set containing 10% of observations that were ommited during refinement.1-d Hydrogens are not included in the dodecamer. Open table in a new tab The atomic resolution achieved with the nonamer data is clearly evident in Fig. 2. The characteristic triplet interaction of this nonamer (12Vlieghe D. Van Meervelt L. Dautant A. Gallois B. Précigoux G. Kennard O. Acta Crystallogr. Sect. D. 1996; 52: 766-775Crossref PubMed Scopus (16) Google Scholar) is shown in the figure. Comparison of the duplex structure of d(GCGAATTCG) with the data obtained at a lower resolution (12Vlieghe D. Van Meervelt L. Dautant A. Gallois B. Précigoux G. Kennard O. Acta Crystallogr. Sect. D. 1996; 52: 766-775Crossref PubMed Scopus (16) Google Scholar) does not show any significant difference (root mean square excluding phosphates between both structures is 0.33 Å). The main difference is that in our study four phosphate groups are disordered and have at least a double conformation. In Fig. 1, only the major conformation is represented. Alternative phosphate positions are available at the reported Nucleic Acid Database file. The strong similarity between the two structures determined at different resolutions gives confidence in the data presently available on oligonucleotide structures that have been obtained mostly at resolutions around 2.5 Å (Ref. 2Shui X. McFail-Isom L. Hu G. Williams L. Biochemistry. 1998; 37: 8341-8355Crossref PubMed Scopus (442) Google Scholar). This is itself an important conclusion of the work reported here, although the most interesting new data obtained relate to the organization of water and ions around DNA, as we will show below. In Fig. 3 we present the minor groove hydration for the Na+, Ca2+, and Mg2+ duplexes. All three spines have been superimposed by using waters P2, P3, and P4 in the primary hydration layer and S3 and S4 in the secondary layer. The nomenclature of Shui et al. (3Shui X. Sines C. McFail-Isom L. VanDerveer D. Williams L. Biochemistry. 1998; 37: 16877-16887Crossref PubMed Scopus (205) Google Scholar) is used. They distinguish four hydration layers at increasing distances from the bottom of the minor groove. From Fig. 3 it is obvious that the superposition of the five water molecules mentioned above is excellent. Waters at either end of the spine (P1, P5) are no longer so well superimposed. Oligonucleotides of different lengths crystallized with different counterions (Na+, Mg2+, Ca2+) in different space groups (P212121, R3) are compared in the figure. It is evident that the central AATT sequence contains a quite rigid spine of hydration, first described by Drew and Dickerson (1Drew H.R. Dickerson R.E. J. Mol. Biol. 1981; 151: 536-556Crossref Scopus (810) Google Scholar), which is very stable. The minor groove is also very narrow in all three cases, although in the nonamer case it is about 0.6 Å wider at the center, as already reported (12Vlieghe D. Van Meervelt L. Dautant A. Gallois B. Précigoux G. Kennard O. Acta Crystallogr. Sect. D. 1996; 52: 766-775Crossref PubMed Scopus (16) Google Scholar). A tertiary layer of hydration is also clear in all cases. Each water molecule in the secondary layer has an additional hydrogen-bonded water molecule. However, the orientation of water molecules in the tertiary layer with respect to those in the secondary layer is different in all three cases. For example, in the nonamer case the S2 water has two associated waters instead of one in the tertiary layer. The quaternary layer of hydration is quite different in all cases. Many of the waters are not hydrogen bonded with those of the tertiary layer as evident in Fig. 3. In fact, they are associated with chains of waters that interact with the phosphate groups of the same and neighbor duplexes. They should not be considered an integral part of the minor groove water spine because their position depends on the interactions in the crystal. In the nonamer crystal structure, the position of water molecules near the P1 side of the spine is very well defined, whereas they are mainly disordered on the P4/P5 side. Such differences are due to the fact that the two ends of the duplexes lie in different regions of the crystal and have different interactions with neighbor duplexes. The water molecules associated with the P1 end of the minor groove water spine form a system of polygons and solvent chains that interconnect three nonamer molecules and several ions (Mg2+, Cl−) in the crystal. The ends of the water spine (sites P1 and P5) are also very different in the three cases shown in Fig. 3, due in part to the presence of divalent cations in these regions. In the case of the nonamer, for example, instead of a single P1 water molecule there are two water molecules at this level, one interacting with cytosine and the other with guanine. The results presented demonstrate that the GAATTC sequence has a very well defined water spine associated with the narrow minor groove of the AATT central region. This water spine has two very well defined and constant layers, with a somewhat variable third layer. On top of the latter layer, a system of water molecules defines a set of pentagons/hexagons and chains of water molecules. The exact geometry depends on the sequence, the length of the duplex, and the crystallization conditions used in each case. The presence of strongly associated water molecules in the A(A/T)T and AT base steps may contribute to stabilizing the conformational features of these base steps, which are known to vary very little (15El Hassan M.A. Calladine C.R. Philos. Trans. R. Soc. Lond. A Math. Phys. Sci. 1997; 355: 43-100Crossref Scopus (176) Google Scholar, 16Subirana J.A Faria T. Biophys J. 1997; 73: 333-338Abstract Full Text PDF PubMed Scopus (40) Google Scholar) in different oligonucleotides. Thus, to interpret the detailed structural features of different DNA sequences, the roles of water and ions should be taken into account. Finally, we should discuss the role of the divalent cations in the structure of the duplexes. The high resolution structure of d(GCGAATTCG) includes several ions (Table I). Because the d(GCGAATTCG) duplex has 16 negative phosphate charges, some charges remain to be neutralized in each asymmetric unit, probably by additional disordered Mg2+/Na+ ions that have not been detected. In fact, some electron density peaks that have been assigned to water molecules may correspond to such ions because they show some short contacts. The Mg2+ ions are mainly involved in the interaction among different duplexes in the crystal, but none of them are found in the region of the minor groove water spine. Instead, two Mg2+ ions are found at both ends of the minor groove and in fact interact with the ends of the water spine, as shown in Fig. 3. A similar situation is found in the R3 structure, where Ca2+ions are present at similar positions, as shown in Figs. 1 and 3. Although the minor groove is considered to be (17Young M.A. Jayaram B. Beveridge D.L. J. Am. Chem. Soc. 1997; 119: 59Crossref Scopus (374) Google Scholar) a very electronegative region, it appears that the geometry of the AATT region with its associated water spine allows neither hydrated Ca2+ nor Mg2+ to penetrate inside the minor groove. However, in oligonucleotides with a different sequence (18Quintana J.R. Grzeskowiak K. Yanagi K. Dickerson R.E. J. Mol. Biol. 1992; 225: 379-395Crossref PubMed Scopus (129) Google Scholar, 19Yuan H. Quintana J.R. Dickerson R.E. Biochemistry. 1992; 31: 8009-8021Crossref PubMed Scopus (124) Google Scholar, 20Goodsell D.S. Grzeskowiak K. Dickerson R.E. Biochemistry. 1995; 34: 1022-1029Crossref PubMed Scopus (56) Google Scholar), which have a wider minor groove, hydrated divalent cations do penetrate into the minor groove. The influence of sequence has also been confirmed by NMR experiments showing that hydrated Mn2+ ions do not penetrate the A4T4minor groove but do penetrate into T4A4(21Hud N.V. Feigon J. J. Am. Chem. Soc. 1997; 119: 5756-5757Crossref Scopus (121) Google Scholar). The eventual substitution of some of the molecules in the water spine by Na+ ions has been a question of debate (2Shui X. McFail-Isom L. Hu G. Williams L. Biochemistry. 1998; 37: 8341-8355Crossref PubMed Scopus (442) Google Scholar, 4Tereshko V. Minasov G. Egli M. J. Am. Chem. Soc. 1999; 122: 470-471Crossref Scopus (167) Google Scholar, 5Tereshko V. Minasov G. Egli M. J. Am. Chem. Soc. 1999; 121: 3590-3595Crossref Scopus (205) Google Scholar, 6Neidle S. Nat. Struct. Biol. 1998; 9: 754-756Crossref Scopus (20) Google Scholar, 22McFail-Isom, L., Sires, C. C., and Williams, L. D.Curr. Opin. Struct. Biol., in pressGoogle Scholar), although it appears that either Rb+ (5Tereshko V. Minasov G. Egli M. J. Am. Chem. Soc. 1999; 121: 3590-3595Crossref Scopus (205) Google Scholar) or K+(3Shui X. Sines C. McFail-Isom L. VanDerveer D. Williams L. Biochemistry. 1998; 37: 16877-16887Crossref PubMed Scopus (205) Google Scholar) may indeed replace, in part, some of the water molecules. In fact, the latter ions have a larger ionic radius more suitable than Na+ for the geometry of the minor groove. In summary, high resolution studies allow an improved knowledge of ion and water distribution around oligonucleotides. However, the relationship between water structure after flash-cooling and water structure at room temperature is not clear, and further studies are required in this direction. In fact, we found that only a limited number of solvent molecules occupies well defined sites, and most of the waters appear to be in a disordered, glassy state. Some of the counterions could not be located, because the oligonucleotide negative charges are not fully neutralized. Also no MPD molecule was found to occupy any definite position. In fact no MPD molecule has been found in any oligonucleotide crystal. In the protein crambin, also studied (23Teeter M.M. Roe S.M. Heo N.H. J. Mol. Biol. 1993; 230: 292-311Crossref PubMed Scopus (118) Google Scholar) at high resolution (0.83 Å); and only one ethanol molecule could be located, although crystals were obtained around 70% ethanol concentration. The absence of MPD in this and in all the reported oligonucleotide structures may indicate that either MPD is excluded from the crystals or is always disordered. We thank Drs. G. DeTitta and J. Luft for advice on crystallization and Drs. V. Tereshko and L. Williams for sending manuscripts before publication." @default.
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• W2085482854 title "Water and Ions in a High Resolution Structure of B-DNA" @default.
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