BIOliVORGAh!ICCHEMIslRY 8,319-329

(1978)

319

Stacking Interactions Between Aromatic Amino Acids and Adenine Ring of ATP in Zinc Mediated Ternary Complexes

JEAN-JACQUES TOULtME Laboratoire de Biophysique du M&urn Notional d ‘Histoire Naturelle, 61, Rue Buffoon, 75005 Par& France

ABSTRACT Spectrophotometrlc studies have provided evidence for zinc-mediated ternary complexes between ATP and aromatic ammo acids. The hypochromicity observed in the 260 nm hand of ATP increased in the order phenyl&nine < tyroslnn < tryptophan. Adding alanlne did not produce any change of the ATP spectrum. The association constant was four fold higher for the ATP-Zinc-Tryptophan complex than for that of the ATP-Zinc-Alanme. The increased stability of the former complex was ascribed to the stacking interaction between indole and adenine rings. The ma&num concentration of the ATPZlnoTryptophan complex occurred at about pH 8.0. For these ternary complexes several possible stacked structures Involving or not involving N(7) of adenine are discussed_

INTRODUCTION The metabolism of nucleic acids requires their highly selective recognition by proteins or enzymes. This implies either direct or indirect specific interactions between parts of these macromolecules_ Amino acid side chains can interact directly with the nucleic acids constitutive elements, i.e., the phosphate-ribose backbone or the nucleic bases. In this respect aromatic amino acids can play a particular role due to their abiity to form stacked complexes with nucleic base rings, as demonstrated by several model system studies [l-6] . Indirect interaction between proteins and nucleic acids may be mediated through a third component, in particular metal cations which are required for many enzymatic reactions. Transition metal cations are of a particular interest because they interact with phosphates and bases at sites which depend both on the metal and on the nucleic acid base [7]. They induce specific structural modifications in nucleic acids [8-12]_ Recent studies have shown that several enzymes involved in nucleic acids replication, repair, transcription, etc, contain functional zinc ion [13-161. Although a great deal of work has been devoted to binary complexes 0 EIsevier North-Holland, Inc., 1978

OOOS-3061/78,‘0008-0319S1.25

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of Zn2* with proteins (and their constituents) or with nucleic acids (and their constituents) [8, 17, 181 much less is known about ternary complexes involving zinc ions proteins and nucleic acids (or their constituents). Interactions between negatively charged polypeptides and polynucleotides have been shown to take place in ternary complexes involving Zn2* or Cu2+ ions [19]. A study of ATPZn (Cu, Mn)-Tryptophancomplexes was recently published by Sigel and Naumarm [3-O] _ In order to determine what type(s) of interactions could be induced through the mediation of metal cations, we have studied the model systems ATP-Zn2+-aromatic amino acids. EXPERIMENTAL Zinc and magnesium acetate were obtained from Merck- Tryptophan and ATP 5’ were purchased from Calbiochem; tyrosine, phenylalanine, histidine, alanine, tryptamine and indole3-propionic acid from Sigma. N(1) methyl tryptophan was synthesized in our laboratory by M. Bazin. U-V. difference spectra were recorded with a Cary 15 spectrophotometer. The following method was used: the sample cell contained the ternary system amino acid + zinc + adenine nucleotide while the reference cell contained the binary system amino acid + adenine nucleotide. Although the recorded spectrum is the superposition of several difference spectra, namely those of the ternary complex (amino acid-Zn-ATP) and binary complexes (amino acid-Zn and ATPZn), these difference spectra provide useful data for a qualitative and comparative study. In order to prevent pH variations, experiments were done in closed vessels under a Na stream. Moreover, all solutions contained 10e2 M Tris and OS M NaC104. This buffer does not qualitatively modify the spectra although complexes iovolving Tris may be present_ To avoid dilution we used relatively large volume (50 ml) and added only a few microliters of concentrated solutions (I-IC104,NaOH, Zn2+, etc). RESULTS

AND DISCUSSION

Formation

of ternary complexes ATP-Zn-Tryptophan

As our method takes into account all complexes formed in the mixed system, we first determined how binary complexes contributed to the U-V. difference spectra. The binary system ATP + Zn 2t has been extensively studied using various techniques and Zn 2* chelation by both phosphate and adenine ringmoieties has been demonstrated [21-25]_ The W difference spectrum of the binary complex has been described by Schneider et al. [223 _ It exhibits a positive band at 275 nm and a negative one at 225 nm (Fig. 1) which are due to a red shift of

STACKING INTERACTIONS AA

IN TERNARY 1

I

‘:

COMPLEXES

321 I

‘-

:-: : I i

+0.04. -

I

t I I

I I I f i : I I

+0.02. -

l.

----a_____---

-0.02. -

t

I

I 250

I

,

I A km)

I 300

FIG. 1. W difference spectra for different systems: ATP (6 X 10M5M) + Zn2* (1.2 X 10m4M) (---), Trp (1.2 X 10e4M) -I- Zn2+ (1.2 X 10w4M) ----)andATP(6X 10e5M)+Zn 2+ (1.2 X 10-4M) i- Trp (1.2 X 10-4M) -)_ Reference solutions were respectively ATP (6 X 10V5M); Trp (1.2 X :-lo-*M); ATP (6 X 10w5M) + Trp (1.2 X 10m4M). The fried circles represent the sum of the two ternary system difference spectra (-a-) and (- - - - -). Medium contained 0.5 M NaCI04, 10-*M Tris at pH 7.6. Under these conditions the binary system ATP + Trp did not give any detectable W difference spectrum. the ATP spectrum. Similar spectra were obtained with AMP, the positive and negative bands being located at 280 and 260 nm, respectively. Addition of tryptophan to adenine nucleotides leads to the formation of stacked complexes [26-28]_ However the association constant is rather low and the concentration used in the present investigation (less than 10-d M for each component) did not allow us to observe the UV difference band described by Morita in the 295 nm region at higher concentrations [28] _

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Tryptophan and Zn2+ ions also form complexes [20] - Under our experimental conditions we observed a difference absorption spectrum which presents a narrow, intense, positive band at 227 nm, a broad negative band at about 260 nm and two other positive bands in the 285-295 nm region. These three last bands are very weak and their intensities are at the limit of detection of our apparatus (Fig. 1). On Fig. 1 is shown the difference spectrum of the ternary system ATP + Zna+ + Trp. It exhibits the narrow positive band at 227 nm characteristic of the Trp-Zn complex, a broad negative band at 255 nm and two weak positive bands whose maxima are about 285 and 295 nm. When compared to the sum of the difference spectra of binary systems (Alp + Zn2+ and Trp + Zn2+) we note an increase1 of the 255 nm band and a decrease at 227 nm and in the 275 nm region. A study of this ternary system has been recently published by Sigel and Naumann [20]_ They observed the 295 nm positive band but the high concentrations (1O-3 M) used in their work did not allow them to obtain any data at shorter wavelengths_ We used intensity variations at 255 nm as a quantitative parameter for the formation of the ternary complex ATP-Zn-Trp. It should be noted however that taking the sum of the difference spectra of binary systems as a reference leads to an underestimate of the ternary complex contribution since the concentration of free zinc ions and consequently that of binary complexes wih be lower in the ternary mixture as compared with the binary ones. In order to obtain information on the stoichiometry of the ternary complex, we added increasing amounts of zinc acetate to mixtures of ATP and Trp with various tryptophan concentrations, ATP concentration remaining constant_ Plotting the absorbance variations at 255 run (I AA 255 I) versus Zn2+ concentration leads to the curves shown in fig. 2. As a reference i 4A 255 1 for zinc addition to ATP alone is given. As previously indicated, 1 AA 255 I values were always higer for the ternary system than for the binary one. Moreover the initial slope of the curves increases with Trp/ATp ratio (Fig_ 2). This means that for a given Zn2+ concentration the higher the tryptophan concentration, the more important is ternary compIex formation. Unfortunately no limiting value was reached under our experimental conditions because precipitation of zinc hydroxyde occurred before f;ill complex formation. Similar results, although less precise, were obtained using absorbance variation at 295 nm instead of 255 nm. The pH dependence of the UV difference spectra was determined for the binary (Trp f Zn2+ and ATP + Zn2*) and ternary (ATP + Zn2* + Trp) systems. Precipitation of zinc hydroxyde was determined by measuring light scattering from the solution The ratio of 44 at two wavelengths (227 and 255 nm) was ’ The expression ‘*increase” and “decrease” for absorbance variations refers to absolute VdUeS.

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FIG. 2. Absorbance variations at 255 nm versus zinc acetate concentration for ATP alone (A) and ATP + Trp mixtures in a pH 7.8, OS M NaCIOa, lo-*M Tris buffer. Trp concentrations: 6 X 10p5M (O), 1.2 X 10m4 M (m), 1.8 X 10V4M (ml_ ATP was 6 X 10e5M in each case. calculated. When precipitation occurred the value of this ratio suddenly changed due to the difference of the scattering contribution at the two chosen waveIengtk The curves obtained when plotting 1 AA 255 1and &I 227 versus pH demonstrate a strong pH dependence of complex formation (Fig. 3). Below pH 6 the absorbance differences are very low at 255 nm or equal to zero at 227 nm. Then &4 increases with pH for all systems. Before precipitation occurs, AA 227 is equal or higher for the Trp + Zn*+ system and I4A 255 I is lower for the ATP + Zn*+ system than for the ATP + Zn *+ + Trp mixture. In the case of the ternary mixture the maximum of absorbance variations is observed for pH 7.8 and 8.0 at 255 run and 227 nm respectively. Therefore the concentration of the ATP-Zn-Trp ternary complex is maximal near pH 8. This value is in relatively good agreement with the result of Sigel and Naumann who found an optimal pH of about 9 from calculation of potentiometric titration curves [20] _ Indole Derivatives and Others Amino Acids UV difference spectra have been recorded for mixed systems containing tryptophan derivatives: tryptamine, indole-3-propionic acid and N(1) methyl trypto-

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AA

I

t

, :

I : f I

o-o& -

:

O.OA--

0.02, -

FIG. 3. pH dependence of absorbance variations at 255 nm (A, 0) and 227 nm (m, 0) for ATP + Zn2+ + Trp (*, o), ATP + Zn2+ (0) and Trp + Zn2+ (m) mixtures. Experiments were performed in a 10V2 M Tris buffer containing 0.5 M NaC104 ([ATP] = 5 X 10V5M; [Zn2*] = lo-*M; [Trpl = 10V4M).

phan. These compounds

were added in two cells: the sample one contained

ATP

and Zn2+, the reference contained only ATT’. The “baseline” was therefore the difference spectrum between ATP-Zn complex and ATP. With tryptamine and indole-3-propionic acid no significant change could be seen. On the contrary important modifications were observed with N(1) methyl tryptophan: the 255 nm negative band was increased (a little more than with tryptophan itself) and three new bands appeared, a negative one at 290 nm and two positive ones at 232 and 307 nm (Fig. 4a). These two latter bands exist also ti the difference spectrum of the N(1) methyl tryptophan-zinc binary system- The band at 232 nm is probably analogous to that observed at 227 in with tryptophan because the absorption spectrum of the N(1) methyl derivatives is red-shifted and broadened as compared to that of tryptophan. The 290 nm negative band seems characteristic of a ternary complex formation involving ATP, Zn2+ and N(1) methyl tryptophan as already suggested by hypochromicity at 255 mn. It therefore appears that the amino and acid groups are needed for ternary complex formation, but that the indole nitrogen is not invoked in zinc cheIation.

STACKING INTERACTIONS I

AA





1

IN TERNARY ’

1



325

COMPLEXES .

I

1

a

I,.

.

=

-,

b

:I /

-

- +0.04

i

- +0.02

- -a02

-0.02 -

-0.04 -

- -0.04

\,!

I

a e I

FIG. 4. (a) W

250

t

I,

1 I1 300

I

250

I

1 I I A(nm)

I

300

.

difference

spectra for ternary systems invoIving 6 X 10V5M i different tryptophan derivatives: 1.28 X iOs4 M tryptamine and 1.16 X 10e4M, indole propionic acid (----), 1.18 X 10-4~. ) and 1.28 X 10m4M N(1) methyl tryptophan (-.-). For tryptophan (comparison the difference spectrum of the binary system 6 X 10m5M ATP + 1.2 X 10W4M Zn2* is given (--.--)(OSM NaC104, 10B2M Tris, pH 7.6). (b) W difference spectra for ternary systems involving 6 X 10B5M ATP + 1.2 X 10B4M Zn2+ + different ammo acids : 1.2 X 10M4M histidine (-.-), 1.25 X 10V4M alanine (- - - - -1, 1.2 X 10M4M phenylalanine(- - - - -), 1.1 X 10m4M ) and W difference spectrum for the binary system ATP (6 X tyrosine (10-5M) and Zn2+ (1.2 X 10-4M)(- - - -)(O.S M NaC104, 10s2M Tris, pH 7.6). ATP + 1.2 X IO-*M

Zn2+

Analogous experiments were performed phenylalanine, tyrosine and histidine. These cations of the UV absorption spectrum (Fig. positive bands appeared with .histidine (227 (219 nm) and a negative one (225 nm) with

with other aromatic amino acids: residues produced several modifi4b). On the short wavelength side, nm), tyrosine and phenylalanine tyrosine. They were also present in

the difference spectra of binary amino acid-zinc systems. Adding tyrosine and phenylalanine did not affect the 275 nm band of the ATP-Zn*+ difference spectra, but it increased the amplitude of the 255 nm negative band indicating formation of ternary compIexes. The case of histidine is very different: the amplitudes of both the 255 nm negative and 275 run positive bands were decreased when this amino acid was added. However the latter decrease is more important than the former one: for ATP and zinc concentrations equal to 6 X 10e5 M and 1.2 X 10s5 M respectively the ratio of the intensities of these two bands varied from l-7 to 2-7 when histidine concentration increased from 6.5 X 10-s M to 3.1 X 10-a M. This

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1 c4

2x10-4 CAMINO

3x104 ACIDI

(M)

absorbance variations at 255 nm versus amino acid concenfor ternary mixed systems: ATE’ (5.6 X 10H5M), Zn** (1.2 X IO-“) and histidine (A), alanine (o) phenylalanine (A), tyrosir,e (O), tryptophm (0) or N(1) methyl tryptophan (II). 1 AA0 255 i is the 255 mu band intensity for the difference spectrum of the binary system 5.6 X 10B5M, ATP + 1.2 X low4 M + Zn*+ (0.5 M NaC104, 10M2M Tris, pH 7.6). FIG_ 5_ Relative

t&ion

could be due in part to the dissociation of the ATE’-Zn complex induced by hi&dine competition for Zn2+ ions (which would lead to a similar decrease of the two bands) and also to a ternary complex formation which would induce an increase in the 255 run band. On figure 5 are shown i AA 255 1variations obtained when increasing amounts of various ammo acids were added to a mixture of ATIP and Zn2+. For a given amino acid concentration we observe a decrease of I AA 255 I in the following order: N(1) methyl Trp z Trp > Tyr > Phe c> His)

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327

It should be pointed out that a circular dichroism study of complexes involving poly(rA) and aromatic amines led to the same order for the decrease of the CD. amplitude of poly(rA), i.e., for the extent of base destacking: tryptamine > tyramine > phenylethylamine > histidine [29] . In order to compare aromatic and non aromatic amino acids, alanine was added to the ATP-Zn2+ mixture. No change in the W absorption difference could be detected (Fig. 4b) although aianine has nearly the same affinity for Zna* ions as tryptophan (KAraZn = 3.2 X 10-4 M-1 and KTrpZn = 4.9 X lO_* M--l in 0.1 M NaClO,; [20]). In order to compare the relative stability of alanine and tryptophan ternary complexes a competition experiment was performed_ Starting from the ternary mixture ATP + Zna+ + Trp, increasing amounts of alanine were added and W absorption difference spectra were recorded_ We observed a decrease of the amplitude of the initial spectrum_ The 1AA 255 i was divided by a factor of two (from binary ATP + Zn2+ system) when a ratio AlajTrp of about four was reached. This means that the association constant of ternary complex is about four fold higher with tryptophan than with alanine. This value agrees quite well with potentiometric data [20] _ Structure

of the ternary complexes

The W difference spectra of the ATP + Zn a+ + aromatic amino acids systems as compared to that of the binary systems ATP + Zn2+ and aromatic amino acids + Zn2+ demonstrate the formation of ternary complexes_ Hypochromicity observed for the ternary mixtures in the 255 nm region could be due either to a red shift of the adenine spectrum or to a stacking of adenine with the aromatic rings of tryptophan, tyrosine, phenylalanine. In a recent PMR study of the ATPZn-Trp system Sigel and Naumann observed an upfield shift of the H (8) resonance of adenine [20]. These authors concluded to the formation of a stacked complex and this agrees well with our W spectroscopic results. Moreover no change in the W difference spectrum of the ATP-Zn system was observed when alanine was added (for which obviously, no stacked structure is possible) although a ternary complex was formed as demonstrated by the competition experiments_ The four fold increased stability of the ATP-Zn-Trp complex with respect to ATP-Zn-Ala may arise from the stacking energy of the purine and indole moieties_ The question now arises of the coordination sites in these ternary adducts. On the amino acid side both the carboxylic and amino groups are involved in Zn2* binding since tryptamine and indole-3-propionic acid do not give stable complexes (in the case of histidine the imidazole ring is certainly involved as well). On the nucleotide side the existence of a complex ATP-Zn involving N(7) of adenine has been postulated [21-25]_ Adding Zn2+ to ATJ? induces a downfield shift of the H(8) resonance of adenine indicating that Zna+ ions bind to N(7) of the purine moiety [20,25] . The binding of Zn2+ ions to phosphate groups only would not be expected to change the absorption spectrum of ATP which is in

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contradiction with experimental observation (Mga’ ions which bind to phosphate groups and do not Interact with the adenine moiety [30,31] do not produce any change in absorbance in binary mixtures). Sigel and Naumann have proposed a model for ATP-Zn-Trp complex in which zinc ions are chelated by I3 and 7 phosphate groups but not to N(7) of adenine ring [20] _ Although the spectral changes for an alteration of the N(7)-Zn 2t interaction are expected to be small such a structure cannot account for the results obtained with alanine_ Actually adding alanine to an ATP + Zn2+ mixture should produce a decrease of the UV difference absorbance spectrum if alanine binding to the ATP-Zn complex would remove chelation of Zn2+ by N(7)_ We did not observe any change when alanine was added. Therefore chelation of zinc in ATP-Zn-Ala ternary complex should involve both phosphate groups and N(7) of adenine ring. But model building studies show that stacking of indole and adenine rings should be very difficult if the same structure was adopted for ATP-Zn-Trp ternary complex. The involvement of a water molecule mediating the interaction between a cation and N(7) has been proposed in the case of Ni2+, Mna+ and Co2+ ions [32] (outer sphere complexes)_ Such a water bridge can certainly form in the case of Zn+-ATP complexes_ Then stacking of adenine and indole rings in ATE’-Zn-Trp ternary complex is possible without disrupting this water bridge. Alternatively the model proposed by Sigel and Naumann could account for our results if from the spectral point of view breaking the N(7)-Zn 2* bond was compensated by the stacking interaction. This would imply that the structure of ATI’-Zn-amino acid ternary compIexes depends on whether the side chain of the amino acid residue is aro-

matic or not. We would prefer the model involving a water molecule bridging the Zn2+ ion to the N(7) of adenine since this model would be acceptable for all amino acids. CONCLUSION Stacked complexes play an important role in many nucleic acids-proteins systems_ They are of course linked to other types of interactions which must exist in macromolecular associations. The residues in the neighborhood of aromatic amino acids may favor such stacked structure (for example lysine in the vicinity of tryptophan leads to a strong association of the tripeptide lysyl-tryptophyl-ar lysine with polynucleotides [14] _ From our results it is clear that a similar role could be played by metal cations which could bring two aromatic rings (an aromatic amino acid and a nucleic acid base) in close proximity so that they could form stacked complexes_ This type of ternary complexes may also induce the formation of other types of non-covalent bonds (Le., hydrogen bonding between nucleic acid bases and some amino acid side chains or the petidic bond) which would not form otherwise in the absence of metal cations because, i.e., of repulsive electrostatic forces in the vicinity of the potentially interacting groups [ 191 _

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I am grareful to Pr. H. Sigel for helpful discussions and to Dr. 8. Cooperman for English correch~ons. I thank Pr. C. H&&e and Dr. Th. Montenay-Garestier for criticism of the manuscript_ I thank also Dr. Bazin for a generousgift of N(i) methyl tryptophan. b

REFERENCES 1. J. L. Dimicoli and C. H&l&e, Biochemistry 13,714-730 (1974). 2. F. Brun, J. J. Tot&& and C. Hilcne, Biochemisfry 14,558~563 (1975). 3. M. Durand, J. C. Maurizot, H. N. Borazan and C. HGBne, Biochemistry 14,563-570 (1975). 4. J. J. Touh& and C. H&ne,.Z. BioL Chem. 252,244-249 (1977). 5. E. J. Gabbay, P. D. Adawadkar and W. D. Wilson, Biochemistry 15,146-151 (1976). 6. E. J. Gabbay, P. D. Adawadkar, L. Kapicak, S. Pearce and W. D-Wilson, Biochemistry 15,152-157 (1976). 7. R. M. Izatt. J. J. Christensen and J. H. Rytting, Chem Reviews 71.439-481 (1971). 8. M. Daune. in Metul Ions in Biological Systems. H. Sigel, ed., M. Dekker, New York, 1974, Vol. 3, p. l-43. 9. G. L. Eichhom and Y. A. Shin,J. Amer. Chem. Sot. 90,7323-7328 (1968). 10. Y_ A. Shin, J. M. Heim and G. L. Eichhom, Bioinorg. Chem. 1,149-163 (1972). 11. Y- A. Shin, BiopoIymers 12,2459-2475 (1973). 12. Ch. Zimmer, G. Luck and H. Triebel, Biopolymers 13,4X-453 (1974). I3_ M. C. Scrutton, C. V. Wu and D. A. GoIdthwait, Proc. Natl- Acad. Sci. 68, 34972501 (1971). 14. J. E. Coleman, Biochem. Biophys. Res. Cor,rmzcn_60,641-648 (1974). 15. D. S. Auld, H. Kawaguchi, D. M. Livingston and B. L. Vallee,Proc. Narl. Acad. Sci. 71, 2091-209s (1974). 16. B- J- Poies. N. Battula and L. A_ Loeb, Biochem. Biophys. Res. Commun. 56,289291 (1974). 17. H. Sigel, in Metal Ions in Biological Sysrems (H. Sigel. Ed.), hf. Dekker, New York (1973) vol. 2, p_ 63-125. 18. R. P. Martin, M. M. Petit-Ramel, and J. P. Scharff, in [17], p. 1-61. 19. C. Hil&e,ZVucleic Acids Res. 2,961-969 (1975). 20. H. Sigel and C. F. Naumann, J. C%em Sot. 98,730-739 (1976). 21. M. Cohn and T. R. Hughes.J_ BioZ. Chem. 237,176-181 (1962). 22. P. W. Schneider, H. Brintzinger, and H. Erlenmeyer, Helv. chim. Acta 47,997-1002 (1964). 23. J. A. Happe and R. L. Ward,J_ Amer. Chem. Sot. 31.4906-4912 (1969). 24. L. Rimai and M. E. Heyde, Biochem. Biophys. Res. Commun. 41, 313-320 (1970). 25. T. A. Glassman, C. Cooper, G. P. P. Kuntz, and T. J_ Swift, FEBS Letters 39,7374 (1974). 26. J. L. Dimicoli and C. HGlt?ne,Biochimie 53,331-345 (1971). 27. K-G. Wagner and R. Lawanek,J_ Mognet. Resonance 8,164-174 (1972). 28. F. Morita, Biochim Biophys. Acta 343, 674-681 (1974). 29. M. Durand, H. N. Borazan, J. C. Maurizot, J. L. Dimicoli and C. Htli?ne. Biochimie 58,394-402 (1976). 30. C. M. Frey and J. E. Stuehr,J_ Amer. Chem. Sot. 94.8898-8904 (1972). 31. S. Tran-Dinh, M. Roux and hf. Ellenberg, Nucleic Acids Res. 2, 1101-1110 (1975). 32. T. A. Glassman, C. Cooper, L. W. Harrison and T_ J. Swift, Biochemistry 10, 843851 (1971). Received March 30, 1977; revised JuZy 7, I977

Stacking interactions between aromatic amino acids and adenine ring of ATP in zinc mediated ternary complexes.

BIOliVORGAh!ICCHEMIslRY 8,319-329 (1978) 319 Stacking Interactions Between Aromatic Amino Acids and Adenine Ring of ATP in Zinc Mediated Ternary Co...
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