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Interactions in a phosphate—water—cation system
Volume 46. number 2
CHEMICAL PHYSICS Lk.TTCRS
1 MJSLh 1977
INTERACTIONSINAPHOSPHATE-WATER-CATIONSYSTEM H.BERTHOD and A. PULLMAN Institut
de Biologre Physico-Chtmique, 75005 Paris. fiance
Laboratoire de Wochlmie 7h~orique auocie’au C N.R S..
Rcccived 26 November 1976
SCI’ ab mitlo study of the system dimethylphosph,tfe anron- WJtcr--NJ* m the supern~oleculeapproach shows the competitlvlty of the through-water binding of NJ* to a phosphodlc\ter hnkap with its dmxt utteraction. Confirm,ttion of :hls ,Guation IPseen in J number of crystal structures of mono- and ohgonucleotldes.
in previous work [I -31, WChave determined the hydration scheme of the drmethylphosphatc anion (DMP-), taken as a model of the phosphodtester linkage m nucleic acids and phosphohpids, using the discrete supermolecule approach [2] m an ab initlo SCF framework. We have also studied in a similar way the characteristics of the direct bmdrng of alkali and alkaline-earth ions to DMP- [4,5]. In the biological milieu, both water and cations are plesent, and the question arises of the possibilities and rnodahties of simultaneous interactions. We present here preliminary results concerning this problem. All the computations have been done using uniformly the SCF ab initio procedure using a standard ST0 3C basis set [6] except for Na+ on which we used our optimal 3G basis [7]. Previous cxpcriencc shows that although the numerical values of the cnergies, distances and electronic populations would be modified by an improvement of the basis [3,7] the characteristic features which emerge from the present study are not likely to be changed. As shown earlier [ I] the first hydration shell of DMP- can accommodate up to SIXwater molecules directly bound to the anion, the most stable hexahydrate comprising three water molecules around each of the anionic oxygens, in a symmetrical disposition (see fig. 1). Table 1 gives the distribution of atomic net charges (obtained in a Mulliken population analysis of the wavefunction of the complex) in the water molecules bound to the phosphate, compared to the correspond-
El4
l-q+ 1. Posittons of the water 111o1eculesin tire hexthydrztc of DMP-. F\phcitly rndtcated art’ the posttions of the wJtcr ouygWs. Ilie not.ition [-xy for the poslt:ons are those of rcfI [ [ I_ lndlcated also 15the sltc of bmding of the sodium ton to this hydrate (\ee texit). nlu dWdnce~ from NJ’ Jre 2.i A to 09 and 06.4.87 A to Oto Jnd 0,; 3.96 K to Ot and 03; 5.91 A to 04; 4.67 A to 02 .md 4.42 A to P.
ing numbers for icolated water and for water bound as a proton donor to another water mo!ecuIe. The molecules bound to the phosphate show a strong polariratron (internal charge displacements) and acquire a partial anionic character (a net ncgativc charge). The Implication of thcsc features for the formation of a second hydration shell has been underlined before [2,3]. It seems probable that they should also have important consequences on the possibilities of cation fixation. 249
CHEMKXL
Volume 46. number 2
Table 1 Net atomic cflarges (mMAectron units) on wdtcr molccUlCs in the hcxahydrate of DMP- compared to rflose of Isolated and dlmcrllcd water a) ____-___-__-_-W
W’
h3 ---_
El4
183 -366 183 0
210 -411 161 -40
235 -469 126 -108 --
233 -450 116 -101
---
lib
0
t12
233 -450 116 -101
f-ff CT -a) W: isolatea water; W’: water bound to the ovygcn of the other molecule m the most stable water dimcr; Er3, Er4, E,z: w.ltcr in the corresponding positions in the DMP-hcuahydrate (see fig. f )_ Ht, N the atom dlrcctfy bound to ?hc oxygen; tfr the other H atom of the bound WJkr a is the total evce~~ cflarge on the bound water molecule.
In order to better visualize the situation WChave eva!uatcd the mulecular clcctrostatic potential [8] of the hexahydrate of DMP-. The Iso-energy con tours in the Ot PO, plane of the phosphate are given in fig. 2.
Fig. 2. Molecular potentid
250
1 March 1977
PHYSICS LElTERS
The anionic character acquired by the water molecules is perceptible in the neighbourhood of the in-plane external water molecules Et, and E,, where the potential minimum appears strongly enhanced (-147.2 kcal/mole) with respect to that of an isolated water molecule (mmimum: -7 t kcal/moIc, fig. 3), or of a water molecule bound to the oxygen of another ncutral water (minimum: -86.2 kcal/mole). Moreover the value of the potential insldc the 0, PO, angle indlcatcs that the attractive character for a positive ion found in this repon for the phosphate itself [9] remains quite large in the hydrated species. The disposition of the inner water molecules of hydration E,,, Et2, I&, E32, is such that they act pairwise so as to mutuaily
reinforce their attractive potential. This can bc seen on the map of fig. 4 drawn in the bisector plane of water E34 whcrc the potential mimmum rcachcs the value -176.8 kcal/mole, and presents thus an cnhancement of about 30 kcal/mole with respect to the corresponding minimum for the in-plane molccuIe E,, , an
in the 01 PO3 plane of the hexahydrAe
of DMP’.
Volume 46. number 2
FQ. 3. Molcwl~ potcntU
CIltMICAL PHYSICS LE-ITERS
In the bisector plant of an Isolated
water molecule.
cnhanccmcnt brought about by the effect of the water molcculc in site E,,. The same effect occurs for the pair El,, E32, on the other side of the 0, PO3 plane. This situation, together with the geometrical disposition of the water molecules, point to the possibility that a cation may find a favorable binding position bctween two water molecules, say ES4 and E,,, in the
hg. 4. Molecular potential in the bisector phne 01’the E34 water molecule in DMP’(H~O)6.
I hfxch 1977
region of maximum attraction along the in?ccsection of the above-considered planes. A search in tkli< rcgior was thus carried out by explicit computation on the DMP----W20),- -Naf system. An equilibrium positio is indeed found for a location of Nat, as sIzowu in fig. 1, at a distance of 2.1 R from the oxygens O9 ant Oh, with a binding energy of --I 39 kcz!:‘male with respect to DMP-(ti20)6. (The energy of direct binding of Na+ to DMP- in its most favorabk position, which is a bridge position in the 0, PO3 plane, is con puted as -. 168 kcal/mole using the same basis set.) A equivalent position exists on tlte other side of the 0, PO3 plane due to the conjugate attraction of the water t~~olccules Ej2 and El 1_ This result indicates that a sodium cation can binr to the phc;sphate anion through an in~ermcdiate moi cule of water, whtch ntay thus be considered to sct-vt at the same time as a water of hydrdtion of the anion and of the cation. This mode of binding of NJ+ allot it to remain surrounded by tltc water molecules of i hydration shell, the same hekg true of the anion, LV of the molecules of water being shared. In the present computation we have not rcopti-
rniled the positicms of the water moIccuks. It is evi dent that in such an optimiration, the hydration
scheme would be distorted; m particular the LWOw molecules E,, and E,, would reorient themsclvcs E as to find a compromise between their most favoral orientation with respect to the anionic oxygens of DMP- and their most favorable orientation with re spect to the sodium ion, at the same time obeying rcquilcnients of minimal repulsion with the other water molecules. The binding energy found is sufficicntiy close TV tlte energy of direct binding to indicate that the bi ing of the cation through a motecute of-waler 1~s. appreciable probability to occur. On the other ban the phenomenon is Iess likely to occur it: the scc31 hydration shell, in which the amounl of anionic cl acter transmitted to the water ntoIccuIes is small12 exemplified in the potential map of fig. 5, and wh the water n~olcculcs arc more loosdy bound [?I _ ntore easily displaced by the cation. A number of experimental data exist which SC{ to confirm the reality of the theoretical findiqs j sentcd here. They come essentiaIIy from X-ray cr lography of nucleotides and oIigonucIcotidcs. ‘fh appears that. as a matter of Fact, direct coordinat
Volume 46. number 2
CHEMICAL PHYSICS LETTERS
1 March 1977
pies correspond to situations more complex than the model case investigated theoretically in this note. Their occurrence illustrates nevertheless the essential proposal of this investigation concerning the compctitivlty of the through-water blndmg of Na+ to a phosphodiester linkage, with its direct interaction.
References [l] A. Pullman, A. Berthod and N. Gresh. Chem. Phys.
Frg. 5. Molecular potential in the bisector plane of the water molecule of the second shell bound to the molecule at Egt in (DMP-)(H20)7.
of the phosphate oxygens to the metal ions is rare in nuclcotide structures and that nletdl ions are frequently only indirectly attached to these oxygens through water bridges [IO]. An outstanding example, involving Na+, concerns the structure of a hydrated monosodium inosinc-S’-phosphate, an unusual nucleotide occurring in the anticodons of tRNh [ 1 I]. Similar results are found in the nucleotide zries with other cations, in particular barium [ 12,131. In the crystal structure of the thymldylyl-(5’+3’)-thymidylate-S’dinucleotide (pTpT) one of the two Na+ 1011spresent is coordinated to the terminal phosphate only through water molecules [ 141. Also in the crystal structures
of the dinu-
cleoside monophosphates: sodium adenylyl-3’,5’-uridine hexahydrate (ApU) [ 151 and sodium guanylyl-3’, 5’-cytidine monohydrate (GpC) [ 161 a cation IS coordinated to the phosphate by both drrect and watermediated links. Of course, these crystallographic exam-
252
Letters 33 (1975) 11. [2] B. Pullman, A. Pullman, H. Berthod and N. Gresh. Theoret. Chum. Acta 40 (1975) 93. [3 J D. Perahia, A. Pullman and Ii. Berthod. Theoret. Chum. Acts 40 (1975) 47. [4] B. Pullman, N. Gresh and H. Berthod. Theoret. Chum. Acta (1975) 71. [S] B. Pullman, N. Gresh, If. Berthod and A. Pullman, Thcoret. Cbtm. Acta, to be published. [6] W.J. Hehre. RF. Stewart and J.A. Pople, J. Chem. Phys 51 (1969) 2657. 171 A. Pullman, H. Bcrthod and N. Gresh, Intern. J. Quantum Chcm. SlO (1976) 59. I81 R. Bonaccorsi, E. Scrocco and J. Tomasi, J. Chem. Phys.
52 (1970) 5270. I’JI H. Berthod and A. Pullman, Chem. Phys. Letters 32 (1975) 233. t101 M.A. Vrswamitra, B.S. Reddy, M.N.G. James and G.J.B. Williams, Acta Cryst. B28 (1972) 1108. 1111 S.T. Rao and M. Sundaratingam, J. Am. Chem. Sot. 91 (1969) 1210. I121 I:‘. Shefter and K.N. Trueblood. Acta Cryst. 18 (1965) 1067. iI31 S. Furberg and A. Mostad, Acta Chem. Stand. 16 (1962) 1627. 1141 N. Camerman. J.K. Fawcett and A. Camerman, Science 182 (1973) 1142. it51 NC. Seeman, J.M. Rosenberg, F.L. Suddath, J.J.P. Kim and A. Rich, J. Mol. Biol. 104 (1976) 109. 1161 J.M. Rosenberg, NC. Seeman. R-0. Day and A. Rich, J. Mol. B~ol. 104 (1976) 145.
CHEMICAL PHYSICS Lk.TTCRS
1 MJSLh 1977
INTERACTIONSINAPHOSPHATE-WATER-CATIONSYSTEM H.BERTHOD and A. PULLMAN Institut
de Biologre Physico-Chtmique, 75005 Paris. fiance
Laboratoire de Wochlmie 7h~orique auocie’au C N.R S..
Rcccived 26 November 1976
SCI’ ab mitlo study of the system dimethylphosph,tfe anron- WJtcr--NJ* m the supern~oleculeapproach shows the competitlvlty of the through-water binding of NJ* to a phosphodlc\ter hnkap with its dmxt utteraction. Confirm,ttion of :hls ,Guation IPseen in J number of crystal structures of mono- and ohgonucleotldes.
in previous work [I -31, WChave determined the hydration scheme of the drmethylphosphatc anion (DMP-), taken as a model of the phosphodtester linkage m nucleic acids and phosphohpids, using the discrete supermolecule approach [2] m an ab initlo SCF framework. We have also studied in a similar way the characteristics of the direct bmdrng of alkali and alkaline-earth ions to DMP- [4,5]. In the biological milieu, both water and cations are plesent, and the question arises of the possibilities and rnodahties of simultaneous interactions. We present here preliminary results concerning this problem. All the computations have been done using uniformly the SCF ab initio procedure using a standard ST0 3C basis set [6] except for Na+ on which we used our optimal 3G basis [7]. Previous cxpcriencc shows that although the numerical values of the cnergies, distances and electronic populations would be modified by an improvement of the basis [3,7] the characteristic features which emerge from the present study are not likely to be changed. As shown earlier [ I] the first hydration shell of DMP- can accommodate up to SIXwater molecules directly bound to the anion, the most stable hexahydrate comprising three water molecules around each of the anionic oxygens, in a symmetrical disposition (see fig. 1). Table 1 gives the distribution of atomic net charges (obtained in a Mulliken population analysis of the wavefunction of the complex) in the water molecules bound to the phosphate, compared to the correspond-
El4
l-q+ 1. Posittons of the water 111o1eculesin tire hexthydrztc of DMP-. F\phcitly rndtcated art’ the posttions of the wJtcr ouygWs. Ilie not.ition [-xy for the poslt:ons are those of rcfI [ [ I_ lndlcated also 15the sltc of bmding of the sodium ton to this hydrate (\ee texit). nlu dWdnce~ from NJ’ Jre 2.i A to 09 and 06.4.87 A to Oto Jnd 0,; 3.96 K to Ot and 03; 5.91 A to 04; 4.67 A to 02 .md 4.42 A to P.
ing numbers for icolated water and for water bound as a proton donor to another water mo!ecuIe. The molecules bound to the phosphate show a strong polariratron (internal charge displacements) and acquire a partial anionic character (a net ncgativc charge). The Implication of thcsc features for the formation of a second hydration shell has been underlined before [2,3]. It seems probable that they should also have important consequences on the possibilities of cation fixation. 249
CHEMKXL
Volume 46. number 2
Table 1 Net atomic cflarges (mMAectron units) on wdtcr molccUlCs in the hcxahydrate of DMP- compared to rflose of Isolated and dlmcrllcd water a) ____-___-__-_-W
W’
h3 ---_
El4
183 -366 183 0
210 -411 161 -40
235 -469 126 -108 --
233 -450 116 -101
---
lib
0
t12
233 -450 116 -101
f-ff CT -a) W: isolatea water; W’: water bound to the ovygcn of the other molecule m the most stable water dimcr; Er3, Er4, E,z: w.ltcr in the corresponding positions in the DMP-hcuahydrate (see fig. f )_ Ht, N the atom dlrcctfy bound to ?hc oxygen; tfr the other H atom of the bound WJkr a is the total evce~~ cflarge on the bound water molecule.
In order to better visualize the situation WChave eva!uatcd the mulecular clcctrostatic potential [8] of the hexahydrate of DMP-. The Iso-energy con tours in the Ot PO, plane of the phosphate are given in fig. 2.
Fig. 2. Molecular potentid
250
1 March 1977
PHYSICS LElTERS
The anionic character acquired by the water molecules is perceptible in the neighbourhood of the in-plane external water molecules Et, and E,, where the potential minimum appears strongly enhanced (-147.2 kcal/mole) with respect to that of an isolated water molecule (mmimum: -7 t kcal/moIc, fig. 3), or of a water molecule bound to the oxygen of another ncutral water (minimum: -86.2 kcal/mole). Moreover the value of the potential insldc the 0, PO, angle indlcatcs that the attractive character for a positive ion found in this repon for the phosphate itself [9] remains quite large in the hydrated species. The disposition of the inner water molecules of hydration E,,, Et2, I&, E32, is such that they act pairwise so as to mutuaily
reinforce their attractive potential. This can bc seen on the map of fig. 4 drawn in the bisector plane of water E34 whcrc the potential mimmum rcachcs the value -176.8 kcal/mole, and presents thus an cnhancement of about 30 kcal/mole with respect to the corresponding minimum for the in-plane molccuIe E,, , an
in the 01 PO3 plane of the hexahydrAe
of DMP’.
Volume 46. number 2
FQ. 3. Molcwl~ potcntU
CIltMICAL PHYSICS LE-ITERS
In the bisector plant of an Isolated
water molecule.
cnhanccmcnt brought about by the effect of the water molcculc in site E,,. The same effect occurs for the pair El,, E32, on the other side of the 0, PO3 plane. This situation, together with the geometrical disposition of the water molecules, point to the possibility that a cation may find a favorable binding position bctween two water molecules, say ES4 and E,,, in the
hg. 4. Molecular potential in the bisector phne 01’the E34 water molecule in DMP’(H~O)6.
I hfxch 1977
region of maximum attraction along the in?ccsection of the above-considered planes. A search in tkli< rcgior was thus carried out by explicit computation on the DMP----W20),- -Naf system. An equilibrium positio is indeed found for a location of Nat, as sIzowu in fig. 1, at a distance of 2.1 R from the oxygens O9 ant Oh, with a binding energy of --I 39 kcz!:‘male with respect to DMP-(ti20)6. (The energy of direct binding of Na+ to DMP- in its most favorabk position, which is a bridge position in the 0, PO3 plane, is con puted as -. 168 kcal/mole using the same basis set.) A equivalent position exists on tlte other side of the 0, PO3 plane due to the conjugate attraction of the water t~~olccules Ej2 and El 1_ This result indicates that a sodium cation can binr to the phc;sphate anion through an in~ermcdiate moi cule of water, whtch ntay thus be considered to sct-vt at the same time as a water of hydrdtion of the anion and of the cation. This mode of binding of NJ+ allot it to remain surrounded by tltc water molecules of i hydration shell, the same hekg true of the anion, LV of the molecules of water being shared. In the present computation we have not rcopti-
rniled the positicms of the water moIccuks. It is evi dent that in such an optimiration, the hydration
scheme would be distorted; m particular the LWOw molecules E,, and E,, would reorient themsclvcs E as to find a compromise between their most favoral orientation with respect to the anionic oxygens of DMP- and their most favorable orientation with re spect to the sodium ion, at the same time obeying rcquilcnients of minimal repulsion with the other water molecules. The binding energy found is sufficicntiy close TV tlte energy of direct binding to indicate that the bi ing of the cation through a motecute of-waler 1~s. appreciable probability to occur. On the other ban the phenomenon is Iess likely to occur it: the scc31 hydration shell, in which the amounl of anionic cl acter transmitted to the water ntoIccuIes is small12 exemplified in the potential map of fig. 5, and wh the water n~olcculcs arc more loosdy bound [?I _ ntore easily displaced by the cation. A number of experimental data exist which SC{ to confirm the reality of the theoretical findiqs j sentcd here. They come essentiaIIy from X-ray cr lography of nucleotides and oIigonucIcotidcs. ‘fh appears that. as a matter of Fact, direct coordinat
Volume 46. number 2
CHEMICAL PHYSICS LETTERS
1 March 1977
pies correspond to situations more complex than the model case investigated theoretically in this note. Their occurrence illustrates nevertheless the essential proposal of this investigation concerning the compctitivlty of the through-water blndmg of Na+ to a phosphodiester linkage, with its direct interaction.
References [l] A. Pullman, A. Berthod and N. Gresh. Chem. Phys.
Frg. 5. Molecular potential in the bisector plane of the water molecule of the second shell bound to the molecule at Egt in (DMP-)(H20)7.
of the phosphate oxygens to the metal ions is rare in nuclcotide structures and that nletdl ions are frequently only indirectly attached to these oxygens through water bridges [IO]. An outstanding example, involving Na+, concerns the structure of a hydrated monosodium inosinc-S’-phosphate, an unusual nucleotide occurring in the anticodons of tRNh [ 1 I]. Similar results are found in the nucleotide zries with other cations, in particular barium [ 12,131. In the crystal structure of the thymldylyl-(5’+3’)-thymidylate-S’dinucleotide (pTpT) one of the two Na+ 1011spresent is coordinated to the terminal phosphate only through water molecules [ 141. Also in the crystal structures
of the dinu-
cleoside monophosphates: sodium adenylyl-3’,5’-uridine hexahydrate (ApU) [ 151 and sodium guanylyl-3’, 5’-cytidine monohydrate (GpC) [ 161 a cation IS coordinated to the phosphate by both drrect and watermediated links. Of course, these crystallographic exam-
252
Letters 33 (1975) 11. [2] B. Pullman, A. Pullman, H. Berthod and N. Gresh. Theoret. Chum. Acta 40 (1975) 93. [3 J D. Perahia, A. Pullman and Ii. Berthod. Theoret. Chum. Acts 40 (1975) 47. [4] B. Pullman, N. Gresh and H. Berthod. Theoret. Chum. Acta (1975) 71. [S] B. Pullman, N. Gresh, If. Berthod and A. Pullman, Thcoret. Cbtm. Acta, to be published. [6] W.J. Hehre. RF. Stewart and J.A. Pople, J. Chem. Phys 51 (1969) 2657. 171 A. Pullman, H. Bcrthod and N. Gresh, Intern. J. Quantum Chcm. SlO (1976) 59. I81 R. Bonaccorsi, E. Scrocco and J. Tomasi, J. Chem. Phys.
52 (1970) 5270. I’JI H. Berthod and A. Pullman, Chem. Phys. Letters 32 (1975) 233. t101 M.A. Vrswamitra, B.S. Reddy, M.N.G. James and G.J.B. Williams, Acta Cryst. B28 (1972) 1108. 1111 S.T. Rao and M. Sundaratingam, J. Am. Chem. Sot. 91 (1969) 1210. I121 I:‘. Shefter and K.N. Trueblood. Acta Cryst. 18 (1965) 1067. iI31 S. Furberg and A. Mostad, Acta Chem. Stand. 16 (1962) 1627. 1141 N. Camerman. J.K. Fawcett and A. Camerman, Science 182 (1973) 1142. it51 NC. Seeman, J.M. Rosenberg, F.L. Suddath, J.J.P. Kim and A. Rich, J. Mol. Biol. 104 (1976) 109. 1161 J.M. Rosenberg, NC. Seeman. R-0. Day and A. Rich, J. Mol. B~ol. 104 (1976) 145.