J. Phys. Chem. 1996, 100, 17797-17800
17797
Platinum-Modified Nucleobase Pairs in the Solid State: A Theoretical Study Paolo Carloni†,‡,§ and Wanda Andreoni*,† IBM Research DiVision, Zurich Research Laboratory, Sa¨ umerstrasse 4, CH-8803 Ru¨ schlikon, Switzerland, and Department of Chemistry, UniVersity of Florence, Via G. Capponi, 7, I-50121 Florence, Italy ReceiVed: June 13, 1996; In Final Form: September 4, 1996X
We present a theoretical study of a mixed adenine-thymine crystal complex of trans-a2 Pt(II) (a ) CH3NH2) with Watson-Crick orientation of the bases, experimentally studied by Krizanovic et al. (J. Am. Chem. Soc. 1993, 115, 5538). Calculations are based on density functional theory with gradient-corrected exchangecorrelation functionals. The results for the structural parameters compare well with X-ray data. The electronic structure near the gap exhibits the characteristic features of a square planar platinum(II) complex with π-acceptor ligands. Comparison with parallel calculations of the nonmetalated base pair helps clarify the role of the trans-a2 Pt(II) moiety.
Introduction The binding of transplatin [trans-diamminechloroplatinum(II)] and its derivatives to DNA is a subject of intense research.1-3 The covalent coordination of the hydrolysis products yields a variety of species, monofunctional adducts, inter- and intrastrand cross-links, and protein-DNA cross-links. Particular attention has recently been paid to interstrand crosslinks, in which the linear trans-Pt(NH3)22+ moiety (or one of its derivatives) replaces an N-H proton of an H-bond between two complementary nucleobases, forming platinum-modified base pairs.4-6 The interest in these cross-links is manifold. Such adducts could be the intermediates in the process of metalinduced denaturation and renaturation of nucleic acids. Moreover, regular substitution of protons forming H-bonds between the bases could be used to generate a “platinum-modified DNA” species. Most importantly, metalated oligonuclotides could be used as antisense drugs that are active toward segments of single-strand DNA. The key question is how and to what extent the insertion of the trans-Pt(NH3)22+ moiety modifies the structure of the nucleobases and the interaction between them. The answer, however, is far from simple. Experimentally, this has been studied by means of synthesis and structural characterization of model compounds, namely, dinucleotide platinum complexes with either Watson-Crick or Hoogsteen orientation of the bases.4-6 Theoretically, a specific investigation of the chemistry of these compounds is still missing. Indeed, for other systems such as cisplatin, important theoretical work has been dedicated over the years to the study of the interaction with DNA, accompanying the huge experimental effort.7 However, whereas realistic models have been treated with classical molecular mechanics and dynamics simulations,8 ab initio calculations have been limited to oversimplified models.9 We apply here an ab initio density functional approach to one of the complexes experimentally investigated by Lippert and co-workers, trans-[(CH3NH2)2 Pt(1-MeT-N3)(9-MeA-N1)](ClO4)‚3.25H2O.4,10 (We will refer to the molecular cation as trans-[a2Pt-AT]+). The accuracy of our scheme has been tested previously on a series of isolated square planar platinum(II) complexes.11,12 In particular, in the case of cisplatin [cis†
IBM Research Division, Zurich Research Laboratory. University of Florence. § Present address: IBM Research Division, Zurich Research Laboratory. X Abstract published in AdVance ACS Abstracts, October 15, 1996. ‡
S0022-3654(96)01738-8 CCC: $12.00
diamminechloroplatinum(II)], transplatin, and carboplatin [cisdiammine-1,1-cyclobutanodicarboxylatoplatinum(II)], the structural and vibrational frequencies obtained were in satisfactory agreement with the available experimental data. Also in the more complex case treated here, our results for the structure are in good agreement with experiment. We have calculated its electronic structure and also that of the AT Watson-Crick base pair. This comparison suggests that the platinum ion plays an important role in the interaction between these two bases. Computational Method The computational scheme is the same as that used for isolated Pt(II) complexes.11,12 The electronic problem is treated with density functional theory using the gradient-corrected exchange and correlation functionals with the Becke-Perdew parametrization.13 Ab initio atomic, angular-momentum-dependent, soft-core pseudopotentials of the Martins-Trouiller type14 describe the core-valence interaction. The electronic wave function basis set consists of plane waves up to an energy cutoff of 70 Ry. Only k ) 0 has been considered representative of the Brillouin zone of the solid. To optimize both electronic wave functions and geometrical parameters, we use the direct inversion in the iterative subspace method15 as implemented by Hutter et al.16 We have taken the parameters of the crystal unit cell of trans[(CH3NH2)2Pt(1-MeT-N3)(9-MeA-N1)](ClO4)‚3.25H2O from experiment4,17 and optimized the positions of all the atoms (134) in it, without imposing symmetry constraints. For the heavy atoms, we took the experimental configuration as the starting point of the optimization. For the initial positions of the hydrogen atoms, which have not been measured, we have made an educated guess. In the case of the AT complex, instead, we have considered it in a fixed structure, namely, the one it assumes in the crystal of the B-DNA decamer C-C-A-A-C-GT-T-G-G.18 Results and Discussion The “Isolated” Watson-Crick AT Base Pair. The isolated H-bonded base pairs have been the subject of extensive ab initio studies,19-23 their main focus being on the energetics of the hydrogen-bond interactions in the various possible conformations, on the stabilization due to the base-base stacking, and on the electronic properties of their radicals. We are interested here in the electronic structure of the Watson-Crick AT base pair in the configuration assumed in © 1996 American Chemical Society
17798 J. Phys. Chem., Vol. 100, No. 45, 1996
Carloni and Andreoni
Figure 1. AT Watson-Crick base pair: (a) Kohn-Sham level diagram (left) of the occupied (solid line) and empty (dashed line) states; and density of the highest occupied states (right) smoothed with a Gaussian of width 0.08 eV. The shaded region represents the contribution of the adenine. E ) 0 eV is the HOMO level. (b) Isodensity contour plots of the HOMO and LUMO (F ) 1.5 × 10-3 (dark) and 1.5 × 10-4 (light) e/Å3).
B-DNA. The H-bond interactions occur between the adenine N1 and thymine N3 (d1 ) 2.8 Å) and the adenine N6 and thymine O4 (d2 ) 3.0 Å).18 Figure 1a plots the Kohn-Sham levels and the density of the occupied states (DOS). The feature of interest here is that these electronic states are localized on either adenine or thymine, as clearly shown by the DOS projected on the individual bases and also by the isoelectronic density contours of the frontier orbitals (Figure 1b). The HOMOs, as well as the LUMO+1, are A orbitals, while the LUMO is localized on T. This type of electronic structure appears to be consistent with the picture one infers from the UV absorption spectra of the A and T residues in poly(dA) poly(dT),24 namely, with the observation of an independent absorption of the two bases. The first ionization process is localized on adenine, and the vertical ionization potential turns out to be 8.1 eV. This value, which accounts for the relaxation of the electronic wave functions, compares well with previous SCF calculations of the Koopmans IP (8.4 eV) for a similar Watson-Crick conformation of the bases.25 Metal-Modified AT Base Pair with Watson-Crick Orientation. The complex studied here is obtained by reacting a derivative of transplatin, [(CH3NH2)2PtCl2], with methylated adenine and thymine (which we shall simply refer to as AT). The X-ray refinement of the crystal corresponds to the space group P1h. There are two molecular units in the unit cell, which are equivalent under rotations of the point group. The refinement, however, does not contain the hydrogens. As the optimization is carried out without symmetry constraints, the space group symmetry of the crystal is lowered from P1h to P1. The final distortion in the optimized structure is negligible. Figure 2 and Table 1 contain the structural information. The orientation of the adenine and thymine bases is that of the Watson-Crick pair. The platinum coordination to AT occurs through the N3 position of the deprotonated thymine and the N1 position of the adenine. Replacement of the hydrogen bond
Figure 2. Structure of the trans-[a2Pt-AT]+ molecular cation. The water molecule bridging the methyl-adenine and methyl-thymine rings is also shown.
with the metal moiety pulls them apart so that d1 ) 4.0 Å and d2 ) 4.8 Å. The major changes on passing from the AT Watson-Crick base pair to the metalated species involve the thymine: the bond angle C2T-N3T-C4T varies from 128° to 123°, and O4T-C4T-C5T from 125° to 122°. Two methylamine ligands complete the coordination of the platinum ion in a slightly distorted square planar geometry, with the maximum deviation (∼7°) pertaining to N1A-Pt-N3T (see Table 1). The good overall agreement between the calculated and the experimental structures confirms the validity of our computational setup and in particular shows its ability to describe the interaction of a platinum complex with the nucleobases in a real environment. Beyond the platinum complex, other molecules present in the cell are the water molecules and the perchlorates. The water molecules also H-bond to the bases and to the perchlorate counterions,4 which are stacked between the platinum complexes. For these species as well, the calculated parameters are in good agreement with experiment. (The root-mean-square displacement from the starting position is 0.39 and 0.24 Å,
Platinum-Modified Nucleobase Pairs in the Solid State TABLE 1: Selected Bond Lengths (Å) and Angles (deg) of the Complex. The Deviation with Respect to Experimental Values Appears in Parentheses. Labels as in Figure 2 Pt-N1 Pt-N2 O2T-C2T N1-C1 N1T-C6T N1A-C2A N2-C2 N3T-C4T N3A-C4A N7A-C5A N9A-C4A N9A-C9A C4A-C5A C5T-C8T N1-Pt-N1A N1-Pt-N3T N2-Pt-N3T C2T-N1T-C6T C6T-N1T-C7T Pt-N1A-C6A C2A-N6A-C6A Pt-N3T-C2T C2T-N3T-C4T C5A-N7A-C8A C4A-N9A-C9A O2T-C2T-N1T N1T-C2T-N3T O4T-C4T-N3T N3T-C4T-C5T N3A-C4A-C5A C4T-C5T-C6T C6T-C5T-C8T N7A-C5A-C6A N1T-C6T-C5T N6A-C6A-C5A N7A-C8A-N9A
2.06 2.07 1.25 1.49 1.37 1.37 1.49 1.39 1.35 1.37 1.37 1.47 1.40 1.49 92 88 90 121 121 126 120 115 123 104 126 119 117 120 118 126 118 122 131 122 125 113
(0.00) (-0.02) (0.00) (-0.01) (+0.01) (0.00) (0.00) (-0.03) (0.00) (-0.02) (-0.02) (0.00) (+0.01) (+0.01) +3 -2 +1 +1 -1 -1 0 0 0 0 -1 -1 -1 -1 0 +2 -1 -1 -1 0 +1 -1
Pt-N1A Pt-N3T O4T-C4T N1T-C2T N1T-C7T N1A-C6A N3T-C2T N3A-C2A N6A-C6A N7A-C8A N9A-C8A C4T-C5T C5T-C6T C5A-C6A N1-Pt-N2 N1A-Pt-N3T Pt-N1-C1 C2T-N1T-C7T Pt-N1A-C2A N1A-C6A-C5A Pt-N2-C2 Pt-N3T-C4T C2A-N3A-C4A C4A-N9A-C8A C8A-N9A-C9A O2T-C2T-N3T N1A-C2A-N3A O4T-C4T-C5T N3A-C4A-N9A N9A-C4A-N9A C4T-C5T-C8T N7A-C5A-C4A C4A-C5A-C6A N1A-C6A-N6A C4A-N9A-C9A
2.03 2.01 1.27 1.39 1.47 1.38 1.39 1.32 1.33 1.33 1.37 1.44 1.36 1.41 178 172 118 118 112 115 118 122 113 106 127 123 127 122 128 106 119 110 118 120 126
(-0.02) (-0.02) (+0.03) (-0.02) (-0.02) (+0.04) (+0.03) (+0.02) (-0.03) (+0.03) (0.00) (+0.01) (+0.01) (+0.04) 0 -1 0 0 -1 -2 +1 0 0 0 0 +1 0 +1 0 -1 -1 +1 -1 +1 -1
respectively26). In particular, the calculation reproduces the expected conformation of the water molecule (“OW1”) (see Figure 2), which assumes a special role by connecting the nucleobases through two H-bonds.27 Knowledge of the electronic properties of this material is of primary importance for the understanding of the effects of
J. Phys. Chem., Vol. 100, No. 45, 1996 17799 metalation. Experimentally, nothing is yet available. We give here a brief description of our results. Figure 3a (left) is a schematic view of the calculated electronic structure in the region of energies close to the energy gap. Figure 3a (right) contains the density of the occupied states on a larger interval and the contributions from the nucleobases, from the amine ligands, and from the platinum d orbitals. The latter is confined to the high energy range. The basic features are those of a square planar platinum(II) complex, where the ligands possess π-orbital systems.28 In particular, the antibonding combination of the metal d orbitals with the “ligand orbitals ” forms the highest occupied states. The LUMO of the isolated systems is formed by the x2 - y2 platinum d component and the σ orbitals of the ligands. In transplatin, it lies ∼3.4 eV above the HOMO.11 In trans-[a2Pt-AT]+, the stronger interaction with the ligands pushes this type of orbitals up by ∼1 eV. Hence in the gap of the metal d states a new band appears, which is localized on the nucleobases. The resulting energy gap is ∼3.2 eV, and it is between “metal” and π “ligand states”, consistent with the acceptor character of the bases. We also note the appearance of additional levels (one in the gap) in the spectrum of the empty states, which corresponds to impurity states localized on the perchlorate. The contribution of the AT ligands to the chemically relevant occupied states is clear in Figure 3a (right). Individual molecular orbitals are shown in Figure 3b. In particular, we note the delocalization on both bases, which can be seen as a metal-induced effect. It contrasts with the picture of the frontier orbitals of the isolated Watson-Crick base pair (see Figure 1), which were localized either on A or on T. This characteristic is kept, instead, for the pure nucleobase orbitals, such as those that form the lowest lying unoccupied band (Figure 3a). In fact, because substitution of the thymine N3-H proton with the trans-[a2Pt]2+ moiety pushes the bases apart, this cannot but disfavor their overlap.
Figure 3. (a) trans-[a2Pt-AT]+: (left) Kohn-Sham band diagram of the chemically relevant states and (right) density of the highest occupied states smoothed with a Gaussian of width 0.08 eV. The shaded region represents the contribution of the platinum d orbitals. E ) 0 eV is the top of the occupied states. (b) Isodensity contour plots of two of the highest occupied states (F ) 1.5 × 10-3 (dark) and 1.5 × 10-4 (light) e/Å3).
17800 J. Phys. Chem., Vol. 100, No. 45, 1996 Conclusions The calculations presented here constitute the first attempt to our knowledge to use ab initio methods to treat a nucleobase interacting with a platinum complex in a real material and may be considered complementary to the experimental investigation. Comparison with experiment for the structural data establishes the validity of the theoretical and computational approaches. The new information that our calculations provide concerns the electronic structure and especially the difference with the nonmetalated base pair. By dominating the highest occupied states, the metal plays a decisive role in the optical and chemical properties of the material. In addition, the platinated system has the characteristics of a charge-transfer crystal complex, with the valence band localized mainly on the metal and with the conduction band of pure nucleobase character. This could be verified with measurement of the absorption and fluorescence spectra in the UV. The present approach appears to be promising for the investigation of the platinum-nucleotide chemistry. We plan to extend it to more complex structural models of the nucleic acids interacting with platinum-based drugs and to the study of their dynamical properties. Acknowledgment. We are indebted to Michele Parrinello for suggesting this study. We wish to thank him and Ju¨rg Hutter for their collaboration at the initial stage of this work. We have used the parallel version of the Car-Parrinello code developed by Ju¨rg Hutter. References and Notes (1) Lippard, S. J. In Bioinorganic Chemistry; Bertini, I., Gray, H. B., Lippard, S. J., Valentine, J. S., Eds.; University Science Books: Mill Valley, CA, 1994; p 564, and references therein. (2) Bruhn, S. L.; Toney, J. H.; Lippard, S. J. Prog. Inorg. Chem. 1990, 38, 477. (3) Brabec, V.; Vra´na, O.; Nova´kova´, O.; Kleinwa¨chter, V.; Intini, F. P.; Coluccia, M.; Natile, G. Nucleic Acids Res. 1996, 24, 336. (4) Krizanovic, O.; Sabat, M.; Beyerle-Pfnu¨r, R.; Lippert, B. J. Am. Chem. Soc. 1993, 115, 5538. (5) Dieter Wurm I.; Sabat, M.; Lippert, B. J. Am. Chem. Soc. 1992, 114, 357.
Carloni and Andreoni (6) Schreiber, A.; Hillgeris, E. C.; Lippert, B. Z. Naturforsch. 1993, 48b, 1603. (7) See, for example: Lippert, B. Progr. Inorg. Chem. 1989, 37, 1. (8) See, for example: Hambley, T. W. Comments Inorg. Chem. 1992, 14, 1. Kozelka, J.; Chottard, J. C. Biophys. Chem. 1990, 35, 165. Dunham, S.; Lippard, S. J. J. Am. Chem. Soc. 1995, 117, 10702. McCarthy, S. L.; Hinde, R. J.; Miller, K. J.; Anderson, J. S.; Basch, H.; Krauss, M. Biopolymers 1990, 29, 823. (9) Krauss, M.; Basch, H.; Miller, K. J. Chem. Phys. Lett. 1988, 148, 577. (10) In this formula, 1-methylthymine anion is abbreviated as 1-MeT, and 9-methylamine as 9-MeA. (11) Carloni, P.; Andreoni, W.; Hutter, J.; Curioni, A.; Giannozzi, P.; Parrinello, M. Chem. Phys. Lett. 1995, 234, 50. (12) Tornaghi, E.; Andreoni, W.; Carloni, P.; Hutter, J.; Parrinello, M. Chem. Phys. Lett. 1995, 246, 469. (13) Becke, A. Phys. ReV. A 1988, 38, 3098. Perdew, J. P. Phys. ReV. B 1986, 33, 8822. Erratum, Ibid. 1986, 34, 7406. (14) Troullier, N.; Martins, J. L. Phys. ReV. B 1992, 46, 1754. (15) Pulay, P. Chem. Phys. Lett. 1980, 73, 393. (16) Hutter, J.; Lu¨thi, H. P.; Parrinello, M. Comp. Mater. Sci. 1994, 2, 244. (17) For the perchlorate ion, one of the two observed orientations was chosen. (18) Prive, G. G.; Yanagi, K.; Dickerson, R. E. J. Mol. Biol. 1991, 177, 217. (19) Clementi, E.; Mehl, J.; von Niessen, W. J. Chem. Phys. 1971, 54, 508. (20) Del Bene, J., J. Mol. Struct. (THEOCHEM) 1985, 124, 201. (21) Aida, M. J. Comput. Chem. 1988, 9, 362 and references therein. (22) Hobza, P.; Sponer, J.; Pola´sek, M., J. Am. Chem. Soc. 1995, 117, 792. (23) Colson, A. O.; Sevilla, M. D. Int. J. Radiat. Biol. 1995, 67, 627. (24) Georghiou S.; Phillips, J. R.; Ge, G. Biopolymers 1992, 32, 1417. (25) Colson, A. O.; Besler, B.; Sevilla, M. D. J. Phys. Chem. 1992, 96, 9787. (26) A table comparing the experimental and calculated water H-bond network is available upon request. (27) The calculated N6A-OW1 and O4T-OW1 distances are 2.88 and 2.59 Å and deviate from experiment by +0.06 and -0.16 Å, respectively. This latter discrepancy may be surprising, in view of the good general agreement for the rest of the structure. It may be due to a combination of several factors, such as a possible limited accuracy of the BP scheme for hydrogen-bond distances and the neglect in our model of the positional disorder in the configuration of the neighboring waters and of the counterions. (28) Gray, H. B. Transition Metal Chemistry; Carlin, R. L., Ed.; Dekker: New York, 1965; p 239.
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