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Adenosine-Proflavine Complex: a Self-Paired Parallel-Chain

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Adenosine-Proflavine Complex: a Self-Paired Parallel-Chain Proc. Natl. Acad. Sci. USA Vol. 77, No. 4, pp. 1852-1856, April 1980 Biochemistry X-ray structure of a cytidylyl-3',5'-adenosine-proflavine complex: A self-paired parallel-chain double helical dimer with an intercalated acridine dye* (non-self-complementary pairing of adenine-adenine and protonated cytosine-cytosine/intercalation dynamics/ sugar-phosphate backbone stereochemistry/frameshift mutagenesis) E. WESTHOF AND M. SUNDARALINGAM Department of Biochemistry, College of Agricultural and Life Sciences, University of Wisconsin-Madison, Madison, Wisconsin 53706 Communicated by David R. Davies, December 31, 1979 ABSTRACT The non-self-complementary dinucleoside parallel-chain double helical dimer of cytidylyl-3',5'-adenosine monophosphate cytidylyl-3',5'-adenosine (CpA) forms a base- (CpA). The dinucleoside monophosphate CpA was chosen not paired parallel-chain dimer with an intercalated proflavine.The dimer complex possesses a right-handed helical twist. The dimer only because it constitutes the end portion of the invariant CCA helix has an irregular girth with a neutral adenine-adenine (A-A) terminus of all tRNAs, but also because it cannot form self- pair, hydrogen-bonded through the N6 and N7 sites (C1'... C1' complementary pairs. separation of 10.97 A), and a triply hydrogen-bonded protonated cytosine-cytosine (C-C) pair with a proton shared between the METHODS base N3 sites (C1'... C1' separation of 9.59 A). The torsion an- EXPERIMENTAL gles of the sugar-phosphate backbone are within their most Single crystals of a 1:1 complex of CpA and proflavine were preferred ranges and the sugar puckering sequence (5' - 3') is grown from an equimolar aqueous solution of proflavine he- C3'-endo, C2'-endo. There is also a second proflavine molecule have space sandwiched between CpA dimers on the 21-axis. Both proflav- misulfate and the sodium salt of CpA. The crystals ines are necessarily disordered, being on dyad axis, and this group P42212 with unit cell parameters a = b = 19.38 (1) A and suggests possible insights into the dynamics of intercalation of c = 27.10 (1) A. Intensity data were collected at 100C with an planar drugs. This structure shows that intercalation of planar Enraf-Nonius (CAD-4) diffractometer. Of the 5214 indepen- drugs in nucleic acids may not be restricted to antiparallel dent reflections measured to a resolution of 0.8 A, 2574 had complementary Watson-Crick pairing regions and provides intensities of at least three standard deviations. The structure additional mechanisms for acridine mutagenesis. was solved by a combination of Patterson techniques, direct The genetic molecules DNA and RNA are targets for various methods (MULTAN) (15, 16), and Fourier synthesis. The chemical agents that possess carcinogenic and mutagenic structure was refined initially by block diagonal least-squares properties. The molecular modes of interactions of these agents analysis with isotropic temperature factors. The discrepancy with the nucleic acid and the effects they produce on the mo- index R (where R = 1IFO|- IFCII/IFo| and Foand Fc are lecular geometry and conformations of DNA and RNA have the observed and calculated structure amplitudes, respectively) been a subject of considerable interest (1-4). X-ray diffraction was 15% for 2460 reflections with the full CpA molecule, the studies of DNA fibers (2, 5) and of co-crystals of self-comple- proflavine molecule, and 10 water molecules (two full sites and mentary dinucleoside monophosphate (6, 7) with the dye eight partially occupied sites). The introduction of anisotropic proflavine have provided important insights on the stereo- temperature factors for the CpA molecule together with the chemistry of intercalation of proflavine into nucleic acids. use of counting statistics for the weighting scheme decreased Because the known single-crystal complexes, in which the dye R to 14%. Full matrix least-squares refinement of the proflavine is intercalated between the base pairs, involve self-comple- molecule and the introduction of five additional partially oc- mentary chains, it was of interest to investigate whether similar cupied water sites decreased R to 12%. The details of the crys- complexes can be formed between dyes and non-self-comple- tallographic refinement will be published elsewhere. mentary nucleic acid fragments. Also, it has been demonstrated that proflavine causes a direct inhibition of protein synthesis RESULTS AND DISCUSSION (8, 9) and that it impairs the enzymic aminoacylation of tRNA CpA Forms a Parallel Dimer with a Protonated C-C Pair (10). Binding studies led to the conclusion that proflavine in- and a Neutral A-A Pair. The asymmetric unit of the crystal hibition of protein synthesis results from strong binding of consists of one CpA molecule (Fig. 1) and one proflavine mol- proflavine to tRNA (11, 12). The evidence for intercalation of ecule. The proflavine of the asymmetric unit consists of two proflavine in tRNA was, however, indirect (11, 12). The binding proflavine molecules lying on the dyad axis at different posi- of proflavine to yeast tRNAPhe was studied by x-ray crystal- tions, each contributing half-weight. The CpA molecules related lography after diffusing proflavine into pregrown crystals of by a dyad coincident with the 42- or 22- axis of the crystal are yeast tRNAPhe (13). Intercalation of proflavine in helical stems self-paired to form a right-handed parallel-chain dimer (Fig. was not found; instead, the binding sites involve electrostatic 2). The two-fold symmetry-related cytosine bases are paired and hydrogen bonding interactions with the polynucleotide with three hydrogen bonds: two between the exocyclic atoms sugar-phosphate backbone (14, t). 02 and N4 and one between the ring nitrogens N3. This pairing Here, we report the crystal and molecular structure of an intercalated proflavine in a novel self-paired right-handed Abbreviations: CpA, cytidylyl-3',5'-adenosine; Tm, amplitude of puckering. The publication costs of this article were defrayed in part by page * Presented at the American Crystallographic Association Summer charge payment. This article must therefore be hereby marked "ad- Meeting, Boston, MA, August 1979, Abstr. S1. vertisement" in accordance with 18 U. S. C. §1734 solely to indicate t Liebman, M. N., Rubin, J. & Sundaralingam, M. (1977) American this fact. Crystallographic Association Meeting Abstracts, East Lansing, MI. 1852 Downloaded by guest on September 25, 2021 Biochemistry: Westhof and Sundaralingam Proc. Natl. Acad. Sci. USA 77 (1980) 1853 observed in the crystal structure of cytosine-5-acetic acid (18) (see also below). The dyad-related adenine bases are paired through the N6 and N7 sites (distance 2.935 + 0.015 A). This pairing scheme between adenine bases has been proposed for acid poly(A) (19) and has been observed in several Ni-protonated adenine nu- cleotide systems (20-23). From the value of the internal angle at N1 and from considerations of charge neutrality (see below), it appears that the adenine bases are neutral. Intercalated and Sandwiched Proflavines. One of the proflavine molecules is intercalated between the C-C and A-A self pairs, whereas the other proflavine is sandwiched between the terminal A-A and C-C pairs of 21-related helical fragments (Fig. 2). Because the proflavine molecules do not have a dyad axis normal to their ring planes, they cannot obey the two-fold symmetry and are necessarily disordered. The intercalated proflavine is two-fold disordered with the dyad axis passing off the center of the middle ring (Fig. 3 Upper). In the case of the N7 sandwiched proflavine, the dyad axis passes through the center of the middle ring, essentially placing the exocyclic amino groups at half-occupancy at four positions (Fig. 3 Lower). Charge Balance. Because no sulfate anion was located in the Fourier maps, the hemiprotonation of the cytosine base implies that the proflavine molecule is hemiprotonated and that the adenine base is neutral, with the charge balance accomplished by the negative charge on the anionic oxygens of the phos- N3~ phodiester group (or C'/2+p-A + proflavinel/2+). Thus, a CpA FIG. 1. An ORTEP (17) drawing of CpA. The atoms are repre- dimer has one net negative charge and the two proflavine sented by their thermal ellipsoids which are scaled to a 20% proba- molecules have together one net positive charge. The disorder bility level. The atom numbering and the notations for the torsion of the proflavines makes it difficult to give a definite identifi- angles are indicated. The gauche+ (g+) domain corresponds to torsion cation of the protonation scheme: either the sandwiched angle values centered on +60°; the trans (t), on 1800; and thegauche proflavine protonated with the intercalated proflavine neutral, (g-), on -60°. or vtice versa, or there was statistical disorder in which the proton was shared between the sandwiched and intercalated scheme strongly suggests that the cytosine bases are hemipro- proflavines. In any case, on an average, half the proflavine tonated, a proton being shared between the N3 nitrogens of molecules are neutral. The loss of one proton by the proflavine dyad-related molecules (N3 ... N3 distance is 2.876 0.015 molecules to the cytosine pair is unexpected in consideration A). A similar pairing scheme between cytosine bases has been of the pK values (24, 25) of proflavine (quaternary nitrogen: 9.7) and of cytidine-5'-phosphate (N3:4.5) and of the pH value of the crystallization solution (n 6.0). However, this apparent anomaly may be explained by the fact that the protonation of the C-C pair leads to a very stable structure, which shifts up- ward the pK of the cytosine base. Indeed, alkaline titration studies of poly(dC) (26) and poly(rC) (27-29) have shown that the pH of the melting transition (pHm) is shifted upwards from the pK of cytosine. It has further been shown that the magni- tude of the shift (pHm minus pK) is proportional to the stability of the base-paired helix-i.e., the melting temperature, Tm (26, 27).
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