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Cation—π and Amino-Acceptor Interactions BetweenHydrated Metal Cations and DNA Bases. A Quantum-Chemical ViewJiří Šponer a , Judit E. Šponer a & Jerzy Leszczynski b

a J. Heyrovský Institute of Physical Chemistry, Academy of Sciences of the Czech Republic ,Dolejškova 3, 182 23 , Prague 8 , Czech Republicb Department of Chemistry and Computational Center for Molecular Structure andInteractions , Jackson State University , Jackson , MS , 39217 , USAPublished online: 15 May 2012.

To cite this article: Jiří Šponer , Judit E. Šponer & Jerzy Leszczynski (2000) Cation—π and Amino-Acceptor InteractionsBetween Hydrated Metal Cations and DNA Bases. A Quantum-Chemical View, Journal of Biomolecular Structure and Dynamics,17:6, 1087-1096, DOI: 10.1080/07391102.2000.10506594

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Cation – πand Amino-Acceptor Interactions BetweenHydrated Metal Cations and DNA Bases.

A Quantum-Chemical View.

http://www.adeninepress.com

Abstract

Cation – π interactions between cytosine and hexahydrated cations have been characterizedusing ab initio method with inclusion of electron correlation effects, assuming idealized andcrystal geometries of the interacting species. Hydrated metal cations can interact with nucle-obases in a cation – π manner. The stabilization energy of such complexes would be largeand comparable to the one for cation – π complex with benzene. Further, polarized watermolecules belonging to the hydration shell of the cation are capable to form a strong hydro-gen bond interaction with the nitrogen lone electron pair of the amino groups of bases andenforce a pronounced sp3 pyramidalization of the nucleobase amino groups. However, incontrast to the benzene – cation complexes, the cation – πconfigurations are highly unsta-ble for a nucleobase since the conventional in plane binding of hydrated cations to the accep-tor sites on the nucleobase is strongly preferred. Thus, a cation – π interaction with a nucle-obase can occur only if the position of the cation is locked above the nucleobase plane byanother strong interaction. This indeed can occur in biopolymers and may have an effect onthe local DNA architecture. Nevertheless, nucleobases have no intrinsic propensity to formcation – π interactions.

Introduction

Metal cations exert a significant influence on the structure, functions, and dynam-ics of nucleic acids (1). The role of cations in neutralizing the negatively chargednucleic acids is well-established (2). However, cations are capable of assumingother roles in nucleic acids. Their effects are often very specific, associated onlywith certain metal cations (3-5). Obviously, significant differences in the electron-ic structures of various cations are important (5-7).

Metal cation interactions in nucleic acids have been intensely investigated byexperimental techniques (1,2,8-14). However, not all aspects of the cation interac-tions can be easily characterized with the available experimental tools. It is thusimportant to complement the experiments with computational studies.Computational studies of interactions between metal cations and biopolymers haveattracted considerable interest in recent years, and the ability for computionalchemistry to describe these interactions has qualitatively improved (5,15-22).

One possibility to investigate the cation binding to DNA is to carry out moleculardynamics simulations. Nanosecond-scale classical molecular dynamics simulationsof hydrated nucleic acids have revealed the ability of cations to migrate into DNAgrooves and to interact with nucleobases (20). This view is supported by NMRstudies (10) while contradicting opinions about these phenomena can be found incrystallographic literature (8,9). MD simulations have been extensively used tocharacterize the role of monovalent cations in the stabilization of four-stranded

Journal of Biomolecular Structure &Dynamics, ISSN 0739-1102Volume 17, Issue Number 6, (2000)©Adenine Press (2000)

Ji rí Sponer,1* Judit E. Sponer1

and Jerzy Leszczynski21J. Heyrovsky Institute of Physical

Chemistry,

Academy of Sciences

of the Czech Republic,

Dolejskova 3,

182 23 Prague 8, Czech Republic2Department of Chemistry

and Computational Center for

Molecular Structure and Interactions,

Jackson State University,

Jackson, MS 39217 USA

1087

*Phone: +420-2-6605-3776;Fax: +420-2-858-2307;E-mail: sponer@indy.jh-inst.cas.cz

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DNA assemblies (19,21). Methods utilizing classical empirical potentials were alsoused to study other aspects of cation – DNA interactions (22).

However, the accuracy of pair additive empirical potentials utilized in MD simula-tions is obviously limited mainly by the neglect of major nonelectrostatic effectssuch as polarization and charge-transfer (5-7,15-18). Their magnitude for divalentcations is comparable to the electrostatic effects at short distances (5,18). Indeed,even for monovalent alkaline earth cations, the polarization term is rather signifi-cant, and its neglect may influence the distribution of cations in the course of MDsimulations (21). Therefore, besides the empirical potential methods, ab initioquantum chemical calculations have been used in studies of interactions betweencations and fragments of biopolymers (5, 15-18). Ab initio methods allow for theconsideration of all nonelectrostatic effects. The accuracy of contemporary ab ini-tio techniques compares well with the gas phase physicochemical experiments(23). Ab initio calculations can also be used for calibration and subsequent verifi-cation of polarization force fields which are orders of magnitude faster than the abinitio method while still keeping accuracy (24).

Ab initio calulations have been instrumental in explaining the specific features ofvarious cations such as the difference between zinc and magnesium (4-6, 7a). It hasbeen demonstrated that the strength of certain hydrogen-bonded base pairs isenhanced via polarization effects upon cation binding (5,15,18). This effect isknown as polarization enhancement of base pairing and has been recently con-firmed by experiments for platinated GC base pairs in DMSO (25).

Cations usually interact with the lone pair H-acceptor atoms of nucleobases eitherdirectly or through water molecules. These water molecules are highly polarizedand their ability to form H-bonds is considerably enhanced (5,18). A recent crys-tallographic study has suggested that cations (hydrated divalent magnesium in thisparticular case) can form a significant through-water cation – π interaction withnucleobases in the double helix exerting a substantial effect on the local DNAarchitecture (8b).

Cation – π interactions have been extensively studied (26). To the best of ourknowledge, however, cation – π interactions have not yet been investigated fornucleobases. In the present paper we analyze the cation – π interaction of cytosinewith hydrated magnesium, zinc, and sodium assuming both idealized and crystalgeometries of the intermolecular complexes. We compare this interaction withanalogous cation – π complexes formed between benzene and a hydrated cation.The cation – π binding mode is further contrasted with conventional in-planenucleobase – cation complexes involving base hydrogen acceptor sites. The calcu-lations show that nucleobases can interact with cations in the cation – π manner,however, only if a geometry constraint is applied. The usual in-plane interactionsbetween cations and nucleobases are strongly preferred. Cytosine – hydrated mag-nesium complexes in the particular crystal geometries (8b) show only a weak inter-action between the cation and cytosine ring, which is not a cation – π contact. Itobviously does not rule out certain long-range electrostatic effects of the cation onthe cytosine position. However, the dominating interaction in the crystal is theusual binding of magnesium to guanines, which basically determines the positionof the ion and its hydration shell with respect to the cytosines.

Method

The molecular structures have been optimized using standard gradient optimizationwithin the Hartree-Fock (HF) approximation. The standard polarized split-valence6-31G* basis set of atomic orbitals (27) has been used for the H, C, N, O, Mg2+ andNa+ species while Zn2+ has been described using Christiansen’s relativisticpseudopotential (28). For some complexes with the cytosine, geometry constraints

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have been applied in order to enforce the cation – π interaction, to keep the inter-molecular geometry frozen according to the experimental structure, or to keep thecytosine planar.

The interaction energies were evaluated using the second-order Møller-Plesset per-turbational method (MP2). The interaction energy is defined as the electronic energydifference between the molecular complex and its monomers separated into infinity.The total MP2 interaction energy consists of two terms: HF interaction energy andcorrelation interaction energy. The HF part of interaction energy includes, amongother contributions, the electrostatic and induction contributions and is dominatingfor systems studied in this paper. The correlation part of interaction energy includesthe dispersion attraction and correction of the electrostatic interaction (5). The inter-action energies in this paper have been calculated for dimers consisting of the aro-matic system (benzene or cytosine) and the hydrated cation.Thus the hydrated cationhas been considered as one subsystem while benzene or cytosine as the other.Because the purpose of the present paper is to obtain a qualitative characterization ofthe cation – π interaction involving nucleobases, we did not decompose the interac-tion energies into the individual pairwise and many body terms (see ref. 5). The inter-action energies were calculated using the 6-31G* basis set with modified d-polariza-tion functions with exponents of 0.25 (29) in order to include the major part of thedispersion attraction. The standard 6-31G* basis set would be deficient in this respect(30). We have used the MP2 procedure instead of the more economical DensityFunctional Theory (DFT) since DFT is not suitable for evaluation of stacking inter-actions (31). Apparently, cation – πcomplexes possess a non-negligible stacking con-tribution. The interaction energies were corrected for the basis set superposition errorusing the standard counterpoise procedure. We did not include the deformation ener-gies of the monomers since these are more than an order of magnitude smaller thanthe interaction energies (5,18).

All calculations were performed using the Gaussian94 (27) suite of programs.

Results

Idealized Geometries. We have first optimized a complex formed by magnesiumhexahydrate and benzene. This system will be used as the reference system forcomparisons with the other systems. The gradient geometry optimization resultedinto a structure with a magnesium cation located above the center of mass of ben-zene at a distance of 4.63Å from the benzene plane (Figure 1). Three polarizedwater molecules in the magnesium hydration shell are oriented towards the ben-zene molecule with the water oxygen and hydrogen atoms separated from the ben-zene plane by 3.41 Å and 2.49Å, respectively. The water hydrogen atoms pointsomewhat nonsymmetrically towards the benzene C–C bonds with the H···C dis-tance towards the two closest carbon atoms being 2.56Å and 2.79Å. Due to thehighly nonadditive nature of the interactions, it is not possible to directly evaluateor separate the energy of the individual O–H···πcontacts (5,18). However, elonga-tion of the O–H bonds involved in the O–H···π contact is rather small, around

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Figure 1: Optimized structure of benzene – magne-sium hexahydrate.

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0.004Å, which is characteristic for weak H-bonds (32). Thus we assume that sta-bility of the system originates in electrostatic interactions between the hydrated ionand benzene possessing a large molecular quadrupole moment (33), and significantinduction contribution can be expected. The benzene – magnesium hexahydratecomplex is consistent with what one could expect for a cation – π complex. Theinteraction energy between the magnesium hexahydrate and benzene amounts to–21.5 kcal/mol and is dominated by the HF component of interaction energy (–17.9kcal/mol).

Then, we have carried out a similar optimization for the cytosine – magnesiumhexahydrate complex. We applied a constraint enforcing the magnesium to be pre-cisely above the center of mass of cytosine (slightly off center of the aromatic ring).No such constraint is necessary for benzene since the position of the cation abovethe benzene center of mass is the genuine minimum. Two optimizations werecarried out (Figure 2). In the first one we constrained all cytosine atoms to becoplanar (Figure 2a). The cation is located 4.53Å above the cytosine plane. Onewater molecule comes as close as 2.93Å to the cytosine plane and forms a weak H-bond with the N3 atom of cytosine with a H···N3 distance of 2.29Å and an elonga-tion of the O–H bond of 0.004Å. There is a second water molecule close to thecytosine plane (3.32Å) located above the cytosine C5 atom. The remaining fourwater molecules do not interact with cytosine. The interaction energy betweenmagnesium hexahydrate and cytosine is practically the same as for the ben-zene complex, –20.2 kcal/mol, with the HF component of –15.3 kcal/mol. Theother optimization (Figure 2b) was done with a full relaxation of the three aminogroup atoms of cytosine, while still keeping the ring planar. This resulted in a con-siderable sp3 pyramidalization of the cytosine amino group. The amino grouphydrogen dihedral angles reached values of 20.1° (N3–C4–N4–H42) and –27.4°(C5–C4–N4–H41). The water molecule situated above the amino group pointedone of its hydrogens towards the amino group nitrogen lone electron pair with aH···N4 distance of 2.69Å. Positions of other water molecules did not change sig-nificantly. Formation of this amino-acceptor interaction improved the interactionenergy to –24.3 kcal/mol (HF part of the interaction energy was –19.0 kcal/mol).

In the subsequent calculation, we have alleviated the constraint enforcing the mag-nesium hexahydrate to interact with the cytosine aromatic system. The complexundergoes a quick rearrangement to the conventional through-water in plane bind-ing pattern of magnesium (Figure 3). This has been accompanied with a drasticimprovement of the interaction energy to –68.2 kcal/mol (the HF component was

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Figure 2: (a) Optimized structure of cytosine – mag-nesium hexahydrate. Mg2+ is constrained to interactwith the cytosine π-system and the cytosine is keptplanar. (b) The same as Figure 2a, however, the cyto-sine amino group is relaxed.

2a

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–68.6 kcal/mol). There is a strong water···N3 H-bond with an Ow···N3 distance of2.89Å and an O–H bond elongation of 0.016Å. In addition, there are twowater···O2 bonds with an Ow···O2 distance of 2.72Å and an elongation of the O–Hbonds of 0.010Å. Note, that all intermolecular distances are obtained within theHF approximation, which slightly overestimates the length of H-bonds.

In order to obtain more information about the systems, we re-optimized the first twostructures (the complex with benzene and the constrained complex with a planarcytosine) while removing the water molecules interacting with the aromatic rings,i.e., three and two water molecules were removed away from benzene and cytosinecomplexes, respectively. In case of the benzene – magnesium complex, we obtaineda classical cation – πcomplex with all water molecules oriented away from the ben-zene and the cation separated by only 2.26Å from the benzene plane (Figure 4). Thetotal MP2 interaction energy between the hydrated cation and benzene improved to–59.9 kcal/mol with the HF part of interaction energy of –59.1 kcal/mol. In the caseof cytosine, however, the distance between the ion and the nucleobase planeremained as large as 3.68Å (Figure 5). One polarized water molecule formed an H-bond towards N3. Distance of the oxygen from the cytosine plane and N3 was 2.73Åand 2.84Å, respectively. Another water molecule formed H-bond with the O2 atom.The distance of the oxygen from the cytosine plane and O2 was 3.12Å and 3.33Å,respectively. The interaction energy improved slightly to –31.2 kcal/mol with HFcomponent of –25.0 kcal/mol. The two optimizations underscore the differencesbetween cytosine and benzene when involved in the cation – π interactions.

Just for a comparison, we have recalculated the interaction energy between a benzenemolecule and a bare Mg2+ cation taking the atomic positions from the optimized geom-etry of the benzene – magnesium-trihydrate complex. The net benzene – Mg2+ interac-tion energy is –108.5 kcal/mol with the HF component of –113.0 kcal/mol. This numbergives a clear picture about the degree of screening exerted by the first hydration shellaround the cation on the strength of the cation – πcomplexes. The complex is charac-terized by large polarization contribution besides the electrostatic term. Similar degreeof water-shell screening exists also for cation – nucleobase interactions (5,18d,24d).

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Figure 3: Unconstrained optimized structure ofcytosine – magnesium hexahydrate.

Figure 4: Benzene – magnesium trihydrate.

Figure 5: Cytosine – magnesium tetrahydrate. Mg2+

is constrained to interact with the cytosine π-systemand the cytosine is kept planar.

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In the next series of calculations, we have repeated the optimizations while replac-ing Mg2+ with divalent zinc and monovalent sodium cations. The three optimiza-tions carried out with zinc resulted in geometries that are virtually identical to thosefor magnesium (Figures 1, 2a, 3). Also the interaction energies were identical,–21.3, –20.2, and –68.1 kcal/mol for the three structures, respectively. The HF com-ponents of interaction energies were –17.8, –15.6, and –68.6 kcal/mol, respectively.For the benzene – sodium hexahydrate complex, we obtained the same structure asshown in Figure 1 although the interaction energy was reduced to –9.1 kcal/mol withthe HF part of the interaction energy of –6.6 kcal/mol. Similarly, for the uncon-strained optimization with cytosine we have obtained the well-known planar com-plex with a hexahydrated cation and two water bridges to O2 atom of cytosine hav-ing interaction energy of –32.8 kcal/mol (HF part of interaction energy is –32.8kcal/mol). For the constrained optimization with cytosine we have obtained a dif-ferent geometry since some water molecules relocated to form conventional H-bonds with either the cytosine or an other water molecule (Figure 6). We did not cal-culate the interaction energy since it was not possible to divide this particular sys-tem into just two subsystems. The subdivision was not possible since one watermolecule is on the other side of the cytosine plane than the others and the cation.Nevertheless, when considering the total electronic energies of the two optimizedcomplexes the unconstrained structure is preferred by 13 kcal/mol over the con-strained one. This again clearly shows that the cation – π interaction is not preferred.

Crystal Geometries. In the next set of calculations, we have investigated the cyto-sine – magnesium hexahydrate interactions reported by McFail-Isom (8b). Figure7 depicts the four closest DNA bases interacting with the magnesium hexahydratein the crystal (coordinates taken from NDB entry BDL084). The hydrated cationforms three strong water bridges with the guanines with donor – acceptor distanceswithin 2.6-2.8 Å. They involve N7 of one of the guanines and O6 atoms of bothguanines. We did not calculate the interaction energies between the magnesium

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Figure 6: Constrained optimization of a complexbetween planar cytosine and hydrated Na+.

Figure 7: Interaction between magnesium hexahy-drate and the closest DNA bases (C1,G2,G22,C21) inthe dodecamer crystal structure (8b).

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hexahydrate and the guanines, but based on our recent calculations (5, 24d) we esti-mate that they are of the order of –70 kcal/mol. This estimate is based on pub-lished interaction energies for inner-shell binding of hydrated cations to guanine(5,18e) and the similar total electronic energies of the inner-shell and through-waterouter-shell hydrated cation – guanine complexes (24d).

The crystal structure further shows that the magnesium hexahydrate is close to twocytosine moieties. It has been suggested that both contacts can be classified ascation – π binding complexes (8b), and thus we have investigated them in moredetails. We have used geometrical constraints (35-38) keeping the position of Mg2+

fixed with respect to the cytosine rings according to the crystal data. The cytosinering and positions of all six water molecules have been fully relaxed (Figures 8aand b). Both complexes show clear similarities. There is one water molecule inter-acting with the cytosine amino-group. The Ow–N4 distance is 3.31Å in the firstcomplex and 3.57Å in the second. These distances are quite long and it means thatthe separation between hydrated magnesium and cytosines is significantly largerthan the separation between the hydrated magnesium and the proximal guanines.The other water molecules do not interact with the cytosine ring.

The cytosine rings are substantially deformed. However, it is not surprising sincethe cytosine ring is known to be very flexible (39,40). The deformation of the ringhas no qualitative effect on the interactions studied; furthermore, it is fair to assumethat within the DNA the deformation would be eliminated due to the adjacentstacked bases. The cytosine amino groups are substantially nonplanar (pyramidal).This finding is again not surprising since the amino groups of isolated bases arepyramidal and very flexible (35,36,38,41). The interaction between the polarizedwater molecule and the lone electron pair of the pyramidal amino group can beclassified as the amino – acceptor interaction (35,37,38). Stabilizing interactionsinvolving nonplanar amino groups of bases, out-of-plane H-bonds and amino

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Figure 8: Interaction between magnesium hexahy-drate and cytosine. Mg2+ – cytosine geometry isfrozen according to the crystal data (8b), otherparameters are optimized. (a) Magnesium hexahy-drate – C1 complex. (b) Magnesium hexahydrate –C21 complex.

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8b

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acceptor interactions, have been object of several previous investigations (35-38, 42).Note, however, that in the crystal structure the water molecules are oriented differ-ently (Figure 7) than in the optimized model complexes (Figure 8) and do not con-tact the amino groups. It is because in the crystal, three polarized water moleculesform strong H-bonds with the guanines. Once these three water bridges are estab-lished, the positions of the remaining water molecules in the octahedral hydrationshell are locked. The observed orientation of water molecules towards the cytosine π-plane and the lack of amino-acceptor interaction between cytosine and the magne-sium hydration shell observed in the crystal should be viewed in this context (43).

The interaction energies between cytosine and magnesium hexahydrate are–13.5 and –8.1 kcal/mol for the two crystal geometries. (The corresponding HFcomponents of interaction energies are –8.5 and –5.6 kcal/mol). These energies areconsiderably less stabilizing than the interaction energy for the idealized cation – πcomplex reported above and almost an order of magnitude weaker than interactionenergies of the through-water in plane complexes between hydrated divalentcations and nucleobases.

We reoptimized the crystal geometries while enforcing the cytosines to be planar.This constraint abolished the amino acceptor interaction and the water reorientedin a way to rather point towards N3. The interaction energies dropped (in absolutevalues) sharply, to –2.5 and –0.3 kcal/mol for the first and second crystal geome-try, respectively, with the HF components of interaction energies being –4.0 and–2.6 kcal/mol. These calculations clearly argue against a cation – π interaction incytosine – magnesium geometries observed in the crystal. The only way to achievea significant attraction between cytosine and hydrated magnesium assuming thismutual arrangement of the interacting species is to form an amino acceptor inter-action between a polarized water molecule and nonplanar amino group of cytosine.Once this H-bond is prevented the interaction becomes insignificant.

Discussion and Conclusions

The calculations provide the following picture of the possibility of cation – π interac-tions involving DNAbases. Hydrated metal cations can interact with nucleobases in thecation – πmanner. The stabilization energy of such complex would be comparable tothat with benzene. However, in contrast to benzene – cation complexes, the cation – πconfiguration is very unstable for a nucleobase since the conventional in plane bindingof the hydrated cation to the acceptor sites on the nucleobase is strongly preferred. Thus,a cation – π interaction with a nucleobase can occur only if the position of the cationis locked above the nucleobase plane by another very strong interaction. This perhapscan occur in biopolymers and the very strong interaction between anionic phosphateoxygens and cations is the most likely primary interaction capable to enforce the cation– base stacking (cf. also Figure 5 in ref. 8b). Nevertheless, nucleobases have no intrin-sic propensity to be involved in cation – π interactions.

The cytosine – magnesium hexahydrate interactions reported recently (8b) arerather weak as the separation between the magnesium cation and cytosines is large.We do not suggest considering them as true cation – πcomplexes. The magnesiumhexahydrate is primarily bound in a conventional way to the acceptor sites of twoadjacent guanines, and these dominating contributions determine the position ofmagnesium and the orientation of its hydration shell with respect to the cytosines.It nevertheless does not rule out certain effect of magnesium on the cytosinegeometries and the local DNA architecture as suggested (8b). Such an influencecan be either directly due to the electric field created by the cation or through mod-ified stacking interaction with the guanines substantially polarized by a stronginteraction with magnesium hexahydrate. Amino-acceptor contribution involvingthe cytosine amino group is also possible, though it seems to be impaired by theprimary binding of the hydrated cation with two guanines.

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Acknowledgements

This study was supported by a grant A4040903 from IGA AS CR (J S), VW-Stiftung I/74657 (J S, JE S), by the National Science Foundation (EHR9108767, J S,JL), the National Institute of Health (Grant. No. GM08047, J S, JL) and grant203/00/0633 by GAOR (J S). We would like to thank Mississippi Center forSupercomputer Research and the Supercomputer Center, Brno for generous allot-ment of computer time.

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43. The magnesium hexahydrate – cytosine geometries shown by the calculations are more favor-able than those observed in the crystal. It is because the structure obtained by the constrainedgradient optimization is obviously the structure with the lowest energy assuming these constraints;other structures are necessarily higher in energy.

Date Received: December 6, 1999

Communicated by the Editor Ramaswamy H. Sarma

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