Crystal structure of pyrogallol[4]arene complex with phosphocholine: A molecular recognition model for phosphocholine through cation–π interaction

Journal of Molecular Structure 1038 (2013) 188–193

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Crystal structure of pyrogallol[4]arene complex with phosphocholine: A molecular recognition model for phosphocholine through cation–p interaction Ikuhide Fujisawa a,⇑, Yuji Kitamura a, Rumi Okamoto a, Kazutaka Murayama b, Ryo Kato c, Katsuyuki Aoki a,⇑ a

Department of Environmental and Life Sciences, Toyohashi University of Technology, Tempaku-cho, Toyohashi 441-8580, Japan Graduate School of Biomedical Engineering, Tohoku University, Aoba, Sendai 980-8575, Japan c Cooperative Research Facility Center, Toyohashi University of Technology, Tempaku-cho, Toyohashi 441-8580, Japan b

h i g h l i g h t s " X-ray analysis of the complex formed between phosphocholine (PCh) and pyrogallol[4]arene (1) as a model for a PCh receptor. " PCh incorporated into the cavity of 1 via cation–p interactions between the trimethylammonium group of PCh and

p-rings of 1.

+

" PCh adopting the gauche conformation, stabilized by the formation of an intramolecular N –Me–H  O hydrogen bond. 2+

" The Ca

ion bound to two molecules of 1 through phenolic hydroxyl groups, forming a Ca2+ ion-bridged dimeric structure of 1.

a r t i c l e

i n f o

Article history: Received 15 July 2012 Received in revised form 10 January 2013 Accepted 12 January 2013 Available online 23 January 2013 Keywords: Crystal structure Phosphocholine Pyrogallol[4]arene Ca2+ Cation–p interaction Molecular recognition

a b s t r a c t Single crystal X-ray analysis of the complex formed between pyrogallo[4]arene (1) and phosphocholine (PCh), [Ca(H2O)3(1)2](PCh)22EtOH5H2O, a model compound that mimics PCh–receptor recognition in biological systems, has shown that PCh is incorporated into the bowl-shaped cavity of 1 through cation–p interactions between the quaternary cationic trimethylammonium group of PCh and p-rings of 1. The hepta-coordinated [Ca(H2O)3]2+ ion is directly bound to two molecules of 1 through phenolic oxygens to form a dimeric molecule of 1, [1{Ca(H2O)3}1]2+. Conformational data of PCh and its derivatives observed in known crystal structures are compiled, focusing on the conformation about the C–C bond in the P–O–C–C–N+ backbone with a reemphasis that the usually observed gauche conformation could be stabilized by an intramolecular N+–C(methyl group)–H  O hydrogen bonding. Ó 2013 Elsevier B.V. All rights reserved.

1. Introduction The quaternary trimethylammonium motif constitutes the head group of a variety of biologically important molecules involving choline and its derivatives like acetylcholine (ACh) as a representative, carnitine, (glycine-, proline-, and c-butyro-) betaines, Ne-trimethyllysine, or muscarine. Since the first report by Sussmann et al. [1a] it has been repeatedly observed in crystal structures that ACh [1], choline [2], phosphocholine [3] (for example, see Fig. S1 in Supplementary materials), carnitine [2e,4], betaines [2e,5], or Ne-trimethyllysine [6] are bound to their receptor- or carrier-proteins at ligand binding sites through cation–p interactions [7] between the cationic head group of the ligand and aromatic residues of the proteins (Table S1). There also exists a wealth of synthetic ⇑ Corresponding authors. Tel.: +81 532 44 6819; fax: +81 532 48 5833. E-mail addresses: [email protected] (I. Fujisawa), [email protected] (K. Aoki). 0022-2860/$ - see front matter Ó 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.molstruc.2013.01.030

receptors for ACh and choline derivatives [7,8], comprised of aromatic walls, involving calix[4]arene [9], resorcin[4]arene [10], or pyrogallol[4]arene [11] hosts, as well as those [10b–d,11] for carnitine (or its derivatives) and those [12] for phosphocholine (or its derivative). However, for such artificial macrocyclic receptor systems, X-ray evidence for the presence of the cation–p interaction is still limited: the only six examples, to our knowledge, are p-sulfonatocalix[4]arene–choline [9a], resorcin[4]arene–ACh [13a], resorcin[4]arene–3-phenylpropionic acid choline ester [13b], and resorcin[4]arene–L-carnitine [13c], tetramethylated resorcin[4]arene–L-carnitine [13c], and pyrogallol[4]arene–L-carnitine [13d] host–guest complexes, other than those [13f,g,14,15] of simple monoquaternary [13f,g,14,15a–g] or diquaternary [15g–i] alkylammonium cations as guests and p-sulfonatocalix[4]arene [14a,14b], resorcin[4]arene [13f,14c,15], tetramethylated resorcin[4]arene [13g], or pyrogallol[4]arene [15j] as hosts. Pyrogallol[4]arenes as well as resorcin[4]arenes have also attracted much attention in supramolecular chemistry as building blocks

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OH HO

Table 1 Crystal data and structure refinements of 1PCh0.5Ca2+ EtOH4H2O.

OH 2-

O3 P

4

O

Formula Formula weight Space group Unit cell dimensions a (Å) b (Å) c (Å) b (°) V (Å3) Z T (K) Ra Rwb GOFc

+ NMe3

Phosphocholine- (PCh- )

Et

(1) Scheme 1.

of a variety of self-assembled nano-capsules [16,17], including a self-assembled hexameric nano-capsule as a representative [16a], or as those of metal–organic nano-capsules (MONCs) [16b,16c]. We report here the crystal structure of a complex formed between pyrogallol[4]arene (1) and phosphocholine (PCh) as a continuation of our X-ray studies [13] of cation–p interactions between the quaternary alkylammonium moiety and the aromatic rings. PCh, a zwitterion compound with the cationic quaternary trimethylammonium head group and the anionic phosphate tail group, is an important intermediate in the lipid metabolism in the cell [18]. Representative reactions in which PCh emerges include the transfer of a phosphate group from ATP to choline by choline kinase [19a], followed by the cytidyl transfer reaction during the pathway of the phosphatidylcholine synthesis [19b] and the decomposition of phospholipids, like sphingomyelin or phosphatidylcholine, by phospholipase C [20]. Solution studies [12,21] on molecular complexation between PCh (or its derivatives) and synthetic receptors have been reported, including calix[6]arenebased cavitand–dioctanoylphosphatidylcholine [12a], resorcin[4]arene-based cavitand–PCh [12b], tryptophan–PCh derivatives [21a], 4,13-diaza-18-crown-6 bearing aromatic sidearms– PCh derivative [22], and cucurbit[7]uril–PCh [8] receptor–ligand systems, where complexations occur through cation–p interactions in the former four cases [12a,12b,21a,22] whereas without cation–p interaction in the last one [8]. A computational study of the preferential interactions of tryptophan with PCh derivatives is also available [21]. Though a relatively large body of crystal structures of PCh derivatives have been studied [24] because of their structural and functional importance as major components of the lipid fraction of cell membranes, to our knowledge, only two crystal structures involving PCh, that is, (PCh)Ca2+Cl4H2O [23a] and [Cu4Cl2(2,20 -bipyridine)4(PCh)2](ClO4)4H2O [23b], and no X-ray example of a host–guest complex of PCh have been reported (see Scheme 1).

2. Experimental

C43H67Ca0.5NO21P 985.00 C2/c 17.524(14) 16.124(13) 34.71(3) 95.710(14) 9759(14) 8 296 0.100 0.249 1.17

a

R = R||Fo|  |Fc||/R|Fo|. Rw = [Rw(|Fo|  |Fc|)2/Rw|Fo|2]1/2. c GOF = [Rw(|Fo|  |Fc|)2/R(M  N)]1/2 (M = No. of reflections and N = No. of variables). b

2.2. X-ray data collection and crystal structure determination Reflection data were collected on a Rigaku AFC-7R diffractometer (at the Instrument Center of the Institute for Molecular Science in Okazaki) with graphite-monochromated Mo Ka radiation (k = 0.71069 Å) at 295 K using a rotating anode generator and a Mercury CCD camera. Data reduction, the cell refinement, and semi-empirical absorption correction were performed with the program CrystalClear [26]. Crystal data and data collection together with structure refinements are summarized in Table 1. The structure was solved using direct methods and refined by full-matrix least-squares techniques on F 2o , minimizing the function Rw(|Fo|  |Fc|)2 with the programs SHELXS [27] and SHELXL [27], respectively, on the platform and graphic software Yadokari-XG [28]. The CH2N+(Me)3 fragment of PCh is disordered at two positions to give two PCh conformers, PCh-A and PCh-B with their occupancy factors of 0.8 and 0.2, respectively, estimated by their electron densities. The Ca atom and two water oxygens (O18 and O22) ride on twofold axes. All non-H atoms were refined with anisotropic thermal parameters. All hydrogen atoms of 1, except for one attached to the terminal methyl carbon C30 of the ethyl group, were determined with difference Fourier maps and refined isotropically without restraints. Any other hydrogen atom was not located in difference Fourier maps and thus not included in the model. Final R and Rw values were 0.100 and 0.249, respectively, with the GOF value of 1.17 (for 7662 reflections with I > 2r(I) out of 10,360 unique reflections in the range 6.6 < 2h < 57.4°). From our experience [13], high R values are common for resorcin[4]arene– or pyrogallol[4]aren–ligand host–guest compounds due to limited quality of crystals, partly caused by an instability out of solution, and the present complex additionally suffers the disordering of the PCh molecule.

2.1. Preparation of the pyrogallol[4]arene–phosphocholine complex 3. Results and discussion Pyrogallol[4]arene (1) host compound was synthesized by an analogous method [25] for resorcin[4]arene. Solutions of 1 and phosphocholine (PCh) were prepared by dissolving 1 (700 mg) in ethanol (42 mL) and phosphocholineCaCl2 (Sigma, 1.0 g) in water (10 mL), respectively. Solutions of 1 (0.1 mL), PCh (2 mL) and water (0.4 mL) were mixed and allowed to stand at room temperature to give dark-orange crystals after 5 days. Molecular formula was determined by X-ray analysis, since elemental microanalysis of this compound was impossible due to its rapid decomposition by loss of crystallization water and/or ethanol molecules.

Interatomic distances and angles in the coordination sphere about the Ca2+ ion and bond lengths and angles of pyrogallol[4]arene (1) and phosphocholine (PCh) molecules are given in Table S2. 3.1. Structure of the pyrogallol[4]arene–phosphocholine complex The asymmetric unit of the complex consists of {[(Ca)0.5(H2O)1.5]1}+(PCh)EtOH2.5(H2O), as shown in Fig. 1, where the

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Fig. 1. A view showing the host–guest-like complexation between 1 and PCh through cation–p interactions and intracomplex hydrogen bonds, where the CH2N+(Me)3 head group of PCh is disordered at two positions, giving the major conformer A and the minor conformer B molecules (see text). Distances (Å) from the carbon atoms of the trimethylammonium group of PCh to the p-centroids of 1 (<4.1 Å): for the conformer A, C38  ring B = 3.76, C39  ring C = 3.32, C39  ring D = 3.78, C41  ring D = 3.91, C41  ring A = 3.51, C38  ring B = 3.76; for the conformer B, C39B  ring B = 3.769, C39B  ring C = 3.64, C40B  ring D = 4.06. Thermal ellipsoids are set at 50% probability. Broken lines denote hydrogen bonds. Note the formation of an intramolecular C41–H  O13 hydrogen bond within PCh (C41  O13 = 2.929(11) Å).

Ca2+ atom, an aqua ligand O18, and a crystallization water molecule O22 ride on twofold axes. The most interesting structural feature is the host–guest-like 1:1 complexation between 1 and PCh, where the CH2N+(Me)3 head group of PCh is disordered at two positions with their occupancy factors of 0.8 and 0.2, one giving the conformer A (comprised of C38, N, C39, C40, and C41), and the other the conformer B (C38B, N, C39B, C40B, and C41), respectively (also see a side view, Fig. S2). The PCh ligand exists as a monovalent anion with the fully deprotonated phosphate group (as evidenced by its bond distances of P–O14 = 1.506(4), P–O15 = 1.519(4), and P–O16 = 1.513(4) Å) and is incorporated into the bowl-shaped cavity of 1 through cation–p interactions between the cationic trimethylammonium head group and p-rings of 1: three carbon atoms C38, C39, and C41 in the conformer A while C39B, C40B, and C41 in the conformer B make close contacts with p-rings of 1 that adopts a usually observed crown conformation stabilized by four intramolecular O–HO hydrogen bonds (Table S4) at the upper rim of the cavitand. In addition, the phosphate tail of PCh is anchored to phenolic oxygens of 1 through two O–HO hydrogen bonds (O2  O15 = 2.702(5) and O3  O15 = 2.577(5) Å). As shown in Fig. 2, the hepta-coordinated [Ca(H2O)3]2+ ion is bound to two molecules of 1 through phenolic oxygen atoms O5 and O6 (Ca–O5 = 2.442(4) and Ca–O6 = 2.477(2) Å) to form a Ca2+ ion-bridged, S-shaped dimer of 1 with the composition of [1{Ca(H2O)3}1]2+, where the Ca2+ and O18 atoms ride on a twofold axis passing through [0, y, 1/4], providing two bowl-shaped scaffolds that act as nests for PCh molecules to give a dimeric complex [PCh{1[Ca(H2O)3]1}2+PCh]. In the crystal lattice, the translation of the unit cell along the a axis creates an interesting molecular array to form a water (O22)-bridged dimeric structure, [1PChH2OPCh1], where O22 rides on a twofold axis passing through

[0.5, y, 1/4] (Fig. 2). In addition, two capping molecules of 1 are indirectly held together, across the twofold axis passing through O22, by a pair of long chain-networks that involve metal-coordination and hydrogen bonds, [1–Ca–O19(H2O)  O17(EtOH)  O21(H2O)  1]2, which act as a fence enclosing water-bridged two PCh ligands. Thus the {1[Ca(H2O)3]1}2+ dimers are self-assembled in a face-to-face orientation to form a non-covalently bonded onedimensional polymer with the composition of {1PChH2OPCh1[Ca(H2O)3]}n along the a-axis through the crystal (see Fig. S3a). This polymeric chain structure is further self-packed side by side with neighboring ones, which are related to the parent one by the symmetry operation of [0.5 + x, 0.5 + y, z] due to the C-face centered lattice, creating a two-dimensional molecular sheet composed of parallelly running polymer chains (see Figs. S3b and S3c). Finally, this molecular sheet is self-connected to neighboring ones, which are generated by the inversion center at [0.25 (or 0.75), 0.25, 0.5], in a tail-to-tail fashion through hydrophobic interactions between ethyl aliphatic chains that are attached to methylene-bridge carbons on the lower rim of 1, forming the bi-layer structure composed of molecular sheets in the whole crystal lattice (see Fig. S3d). The 1H NMR spectrum (400 MHz, 293 K; Fig. S4) of the CD3ODD2O (1:1) solution containing 1 (saturated concentration) and PCh (0.1 mmol dm3) shows a singlet at d 2.276 ppm for the N-methyl protons of PCh, while the corresponding signal of PCh alone appears at d 3.240 ppm. This upfield shift of 0.964 ppm for the complex is probably due to the aromatic ring-current effect, indicating that the quaternary trimethylammonium group associates preferentially with the p-rings of 1 in solution. In addition, the titration data obtained for the chemical shift change of the Ha proton (Scheme 1) of 1 were fitted to a 1:1 binding model to give the binding constant of 61 ± 17 M1 for the PCh–1 complexation. 3.2. Conformations of phosphocholine Sundaralingam in 1972 [29a] and Pascher et al. in 1981 [24d] and 1992 [24g] reviewed crystal structures of phospholipid constituents, showing that the P–O–C–C–N+ backbone prefers the gauche conformation about the C–C bond by virtue of electrostatic interaction between the electronegative oxygen and the quaternary nitrogen. Table 2 summarizes conformational data of PCh and its derivatives and PCh in PCh–protein (but excluding PCh derivatives) complexes, including more recent in addition to the previous [29a,24d,g] data (some examples are drawn in Fig. S5). The values of the O–C–C–N+ torsion angle show that the gauche conformation is always observed in the present complex (the torsion angles O13–C37–C(38 or 38B)–N = 76.7(12) or 66(3)° for the conformers A or B, respectively, and the interatomic O13  N and O13  C41 distances of 3.162(6) and 2.929(11) Å for both the conformers A and B), a copper–PCh complex [23b], PCh derivatives [24], and even in protein–PCh complexes [3a–d,f–h], except for the near-gauche conformation (with the torsion angle of 103.6°) in one of the two PCh molecules in the copper complex [23b] and the trans conformation in complexes of C-reactive protein [3e] and MC/PC603 Fab [3i]. For PCh and its derivatives with the gauche conformation, the absolute values of observed O–C–C–N+ torsion angles distribute in the range of 42–88° and P–O–C–C torsion angles in the range of 85–275(=85)° (Table 2). The conformation about the C–C bond is more simply describable in the term of the interatomic O  N+ distance: the distances fall into the relatively limited range of values of 2.9–3.3 Å with the average of 3.12(11) Å for 27 examples with the gauche conformation, 3.3 Å with the near-gauche conformation [23b], and longer than 3.8 Å with the trans conformation [3e,i]. In addition, a computational study of PCh–tryptophan 1:1 and 1:2 complex formation systems has predicted [21b] that PCh predominantly adopts the gauche

I. Fujisawa et al. / Journal of Molecular Structure 1038 (2013) 188–193

191

Fig. 2. A view (down along the b-axis normal to the paper-plane) showing the Ca2+ ion-bridged, twofold symmetry-related dimeric complex [PCh{1[Ca(H2O)3]1}2+PCh] and the ligand-mediated assembly of 1 into the dimeric structure [1PChH2OPCh1], where a pair of PCh ligands are connected to each other through a water(O22)bridge. PCh ligands are drawn only for the conformer A (major counterpart) for clarity. Broken lines denote hydrogen bonds.

conformation. These data suggest that the gauche conformation is not only the intrinsic nature of PCh itself (and its derivatives) due to electrostatic O  N+ interaction, but is also a bioactive form. It should be noted here that the predominance of the gauche conformation also holds for the closely related C–O–C–C–N+(Me)3 system of ACh [29b] and its cholinergic agonists [30] like carbachol and even muscarine, as originally pointed out as early as 1986 by Sundaralingam [29b] and Pauling et al. [30]. Importantly, these authors also showed that PCh molecule may form an intramolecular N+–C(methyl)–H  O hydrogen bonding, which may be highly electrostatic in character since the positive charge on the nitrogen atom would be delocalized in the methyl groups [29b], in accordance with ab initio molecular orbital calculations of electron distribution in the N+(Me)4 ion [31]. In order to form such an N+–C– H  O hydrogen bond, the direction of the two tetrahedral electron pairs on the ester oxygen is crucial for accepting a hydrogen from the nearest methyl group [30], and thus the observed P–O–C–C torsion angles are restricted in the range of 85–275° when PCh adopts the gauche conformation about the C–C bond (Table 2). 3.3. Coordination properties of Ca2+ ion The present experimental system contains 1 and PCh as possible ligands that could coordinate to Ca2+ ion. Possible metal binding sites are phenolic oxygens and p-rich cavity of 1 and phosphate oxygens of PCh. For example, Ca2+ ion is bound to the phosphate group of PCh in the C-reactive protein complex [3e] (unfortunately, no atomic coordinates are available for (PCh)Ca2+Cl4H2O [23a]). On the other hand, computational studies [32] have repeatedly demonstrated that cation–p interactions occur to considerable extent between alkali and alkaline earth metal ions involving Ca2+ and aromatic motifs. Thus we can expect that Ca2+ ion may compete with the cationic N+(Me)3 head moiety in terms of cation–p interaction since the cavity size of 1 (with the width at the upper ring being 8.4–8.7 Å) is enough for a spherical Ca2+ ion

(with the ionic radius of 0.99 Å [33]) to locate within the cavity. In practice in the present complex, Ca2+ ion is bound neither to PCh nor to p-rings of 1 but to the phenolic hydroxyl groups of 1. This suggests that cation–p interaction within the cavity of 1 might be more effective with the N+(Me)3 cation than with Ca2+ ion. The Ca2+ binding to the phenolic hydroxyl group is of special interest because it usually binds to the deprotonated phenolic oxygen (for example, in the crystal structure of [Cu2Ca2(N-3-carboxylsalicylideneglycylglycinato)(H2O)6]2H2O [34]), alchoholic hydroxyl, ether, keto, or carboxyl oxygens (for example, the last four types of Ca2+–O bondings are formed in a polyether ionophore complex Ca(ionomycin2) [35]; refer a review [36] for details involving structures and bondings of Ca2+ ion in biological systems). 3.4. Biological relevance of the pyrogallol[4]arene–phosphocholine complex The survey of the Protein Data Bank (PDB) shows that, in all of the nine crystal structures [3] of proteins containing PCh as ligand, the CH2N+(Me)3 head of the ligand always makes close contacts with one or plural aromatic residues at its binding sites of the proteins (see Table S1 and Fig. S1). Among these protein structures, one [3a–c,e,f], two [3d,h,i], or three [3g] aromatic residues participate in close contacts with the CH2N+(Me)3 group of the ligand. Tryptophan and/or tyrosine residues commonly play such a role, except for one complex [3e] for which phenylalanine is involved. In each complex structure, one or two carbon atoms of the CH2N+(Me)3 group locate above the aromatic ring-face with the shortest distance to the carbon atom of the aromatic ring being from 3.1 to 3.9 Å, indicating the existence of the cation–p interaction [7]. Although the overall structures of the proteins and the architectures of the PCh binding sites vary, the conservation of the cation–p interaction in these complex structures strongly suggests the importance of the cation–p interaction in the recognition and the binding of PCh.

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Table 2 Conformational dataa of PCh, its derivatives, and PCh in complexes with proteins in known crystal structures. Complex

Torsion angles (°)



2+

Pyrogallol[4]arenePCh 0.5Ca EtOH4H2O 

[Cu4Cl2(bpy)4(PCh )2](ClO4)4H2O LL-

a-glycerophospho-cholineCdCl23H2O a-glycerophospho-choline

2,3-Dimyristoyl-D-glycero-1-phosphocholine2H2O 3-Lauroylpropandiol-1-phosphocholineH2O Octadecyl-2-methyl-glycero-phosphocholineH2O 3-Palmitoyl-D-glycero-1-phosphocholineH2O 3-Hexadecyl-D-glycero-1-phosphocholineCHCl3 IsobutylphosphocholineH2O IsobutylphosphocholineIsobutanol Isobutylphosphocholine (cholesterol)3(isobutanol)3 CDP-cholineNa+4H2O Potassium channel 10–PCh Choline binding protein E-PCH Teichoic acid phospho-choline esterase–PCh Sticholysin II actinoporin-PCh C-Reactive protein–PCh

Leukocidin F–PCh Coline kinase alpha2–PCh PDC-109 fibronectin–PCh

MC/PC603 Fab–PCh a b c d e f g h i

Interatomic distances (Å)

CCDC No. or CSD code or PBD ID

Ref.

813984

This work

624676

[23b]

P–O–C–C

O–C–C–N+

C–C–N+–Meb

O  N+

O  Meb

Mol.1 Mol.2c Mol.1 Mol.2

178.0 125 174.8 -165.8 178d

76.7 66 103.6 88.1 73d

63.2 -72 -77.9 78.1 –e

3.16 3.16 3.25 3.03 3.04d

2.93 2.93 3.08 2.75 2.96d

GLYCACe

[24a]

Mol.1

-138

73

68

3.13

3.03

GLPCHO

[24b]

Mol.2 Mol.1

140 143f 150f 130 176 144g 149g 138g 141g 131.5i 132.1i 92.0 168.4 139.3 146.5 154.7 159.0 179.2 179.3 169.1 164.1 161.1 161.4 176.7 179.8 85.7 91.0 143.1 156.5 173.0 177.5 52.1

75 64f 54f 84 72 77g 72g 69g 69g 72.0i 77.4i 70.4 66.7 55.6 80.7 69.0 83.6 73.5 42.1 176.1 169.9 150.5 141.0 150.7 60.6 73.1 61.9 88.1 47.9 76.2 78.4 163.3

68 –e –e 87 72 –e –d –d –d 64.7i 61.4i 69.0 70.4 66.6 19.1 22.1 12.2 93.0 83.3 14.3 46.9 43.5 80.9 31.7 80.5 67.8 63.4 43.1 85.0 73.9 74.7 58.2

3.14 3.21f 3.18f 2.85 3.13 –e –d –d –d 3.13i 3.19i 3.10 3.05 3.11 3.27 3.26 3.16 3.22 3.01 4.06 3.99 3.77 3.98 3.91 2.99 3.15 3.03 3.26 2.96 3.12 3.17 3.75

3.04 –e –e 2.91 3.06 –e –d –d –d 2.93i 2.99i 2.93 2.92 2.90 3.44 3.39 3.24 3.41 3.10 4.31 4.52 3.99 4.21 4.24 2.92 3.02 2.86 3.08 3.05 3.02 3.09 4.08

WAHQAXe

[24c,d]

LYPCHL DONZAH –h

[24e] [24f] [24g,h]

–h

[24g,h]

c

Mol.1 Mol.2 Mol.1 Mol.2

Mol.1 Mol.2 Mol.1 Mol.2 Mol.1 Mol.2 Mol.3 Mol.4 Mol.5 Mol.1 Mol.2 Mol.1 Mol.2 Mol.3 Mol.4

h

– –h MEQKAU CYPCHO01 2X6C 1WRA

[24i] [24i] [24j] [24k] [3a] [3b]

2BIB 1O72

[3c] [3d]

1B09

[3e]

3LKF 2CKQ

[3f] [3g]

1H8P

[3h]

2MCP

[3i]

The numerical values were calculated using atomic coordinates registered in CSD or PBD files, unless otherwise noted. The methyl group that is the closest to the ester oxygen atom in the P–O–C–C–N+(Me)3 backbone. Mol.1 and Mol.2 correspond to the conformer A and the conformer B in the text, respectively. The numerical values are from [24a]. No atomic coordinates were available. The numerical values are from [24d]. The numerical values are from [24h]. No CSD code was available. The numerical values were calculated using atomic coordinates given in [24i].

The present complex mimics cation–p interactions between PCh and its receptors in biological systems in the sense that the CH2N+(Me)3 head group of PCh locate above p-faces of 1 with close contacts being from 3.32 to 4.06 Å (Fig. 1). In addition, it is of interest to note here that the tail moiety of the PCh ligand also interacts with the same ring of 1 through O(phosphate)  HO(ring A) hydrogen bonding. This is reminiscent of similar interactions with the tyrosine residue at the PCh binding site in sticholysin II actinoporin complex [3d] (see Fig. S6) or at the cytidyldiphosphocholine (CDPcholine) binding site in CTP:phosphocholine cytidylyltransferases [37]; in the latter complexes [37], the b-phosphate-choline moiety of CDP-choline takes part in the corresponding situation (see Fig. 3B in Ref. [37a] or Fig. 5D in Ref. [37b]).

trimethylammonium group of phosphocholine and p-rings in the synthetic receptor–phosphocholine system that mimics interactions between the trimethylammonium group and the aromatic residue(s) at the phosphocholine binding site in proteins. The terminal quaternary N+(Me)3 functional group of the O–C–C–N+(Me)3 choline system is doubly of biological significance, one taking part in the stabilization of the biologically active gauche conformation of the molecule through the formation of an intramolecular N+Me–H  O(ester oxygen) hydrogen bond and the other participating in the molecular recognition of PCh by its receptors through the intermolecular cation–p interaction.

Appendix A. Supplementary material 4. Conclusions This study provides the first X-ray example that shows the existence of cation–p interaction between the quaternary cationic

Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.molstruc.2013.01. 030.

I. Fujisawa et al. / Journal of Molecular Structure 1038 (2013) 188–193

References [1] (a) J.L. Sussman, M. Harel, F. Frolow, C. Oefner, A. Goldman, L. Toker, I. Silman, Science 253 (1991) 872; (b) P.H.N. Celie, S.E.V. Rossum-Fikkert, W.J.V. Dijk, K. Brejc, A.B. Smit, T.K. Sixma, Neuron 41 (2004) 907; (c) M. Brams, E.A. Gay, J.C. Sáez, A. Guskov, R.V. Elk, R.C.V.D. Schors, S. Peigneur, J. Tytgat, S.V. Strelkov, A.B. Smit, J.L. Yakel, C. Ulens, J. Biol. Chem. 286 (2011) 4420. [2] (a) J.A. Hermoso, B. Monterroso, A. Albert, B. Galán, O. Ahrazem, P. García, M. Martínez-Ripoll, J.L. García, M. Menéndez, Structure 11 (2003) 1239; (b) Y. Cai, C.N. Cronin, A.G. Engel, K. Ohno, L.B. Hersh, D.W. Rodgers, EMBO J. 23 (2004) 2047; (c) E. Malito, N. Sekulic, W.C.S. Too, M. Konrad, A. Lavie, J. Mol. Biol. 364 (2006) 136; (d) M. Pittelkow, B. Tschapek, S.H.J. Smits, L. Schmitt, E. Bremer, J. Mol. Biol. 411 (2011) 53; (e) Y. Du, W.-W. Shi, Y.-X. He, Y.-H. Yang, C.-Z. Zhou, Y. Chen, Biochem. J. 436 (2011) 283. [3] (a) O.B. Clarke, A.T. Caputo, A.P. Hill, J.I. Vandenberg, B.J. Smith, J.M. Gulbis, Cell 141 (2010) 1018; (b) G. Garau, D. Lemaire, T. Vernet, O. Dideberg, A.M.D. Guilmi, J. Biol. Chem. 280 (2005) 28591; (c) J.A. Hermoso, L. Lagartera, A. Gonzalez, M. Stelter, Nat. Struct. Mol. Biol. 12 (2005) 535; (d) J.M. Manchnˇo, J. Martín-Benito, M. Martínez-Ripoll, J.G. Gavilanes, J.A. Hermoso, Structure 11 (2003) 1319; (e) D. Thompson, M.B. Pepys, S.P. Wood, Structure 7 (1999) 169; (f) R. Olson, H. Nariya, K. Yokota, Y. Kamio, E. Gouaux, Nat. Struct. Biol. 6 (1999) 134; (g) E. Malito, N. Sekulic, W.C. Too, M. Konrad, A. Lavie, J. Mol. Biol. 364 (2006) 136; (h) D.A. Wah, C. Fernández-Tornero, L. Sanz, A. Romero, J.J. Calvete, Structure 10 (2002) 505; (i) E. A. Padlan, G. H. Cohen, D. R. Davies, PDB ID: 2MCP; unpublished work. [4] (a) G. Jogl, L. Tong, Cell 112 (2003) 113; (b) G. Jogl, Y.-S. Hsiao, L. Tong, J. Biol. Chem. 280 (2005) 738; (c) A.C. Rufer, R. Thoma, J. Benz, M. Stihle, B. Gsell, E.D. Roo, D.W. Banner, F. Mueller, O. Chomienne, M. Hennig, Structure 14 (2006) 713; (d) L. Tang, L. Bai, W.-H. Wang, T. Jiang, Nat. Struct. Mol. Biol. 17 (2010) 492. [5] (a) C. Ziegler, E. Bremer, R. Krämer, Mol. Microbiol. 78 (2010) 13 (and references therein); (b) I.K.H. Leung, T.J. Krojer, G.T. Kochan, L. Henry, F.V. Delft, T.D.W. Claridge, U. Oppermann, M.A. McDonough, C.J. Schofield, Chem. Biol. 17 (2010) 1316; (c) B. Tschapek, M. Pittelkow, L. Sohn-Bösser, G. Holtmann, S.H.J. Smits, H. Gohlke, E. Bremer, L. Schmitt, J. Mol. Biol. 411 (2011) 36. [6] (a) H.T. Li, S. Ilin, W.K. Wang, E.M. Duncan, J. Wysocka, C.D. Allis, D.J. Patel, Nature 442 (2006) 91; (b) P.V. Pena, F. Davrazou, X.B. Shi, K.L. Walter, V.V. Verkhusha, O. Gozani, R. Zhao, T.G. Kutateladze, Nature 442 (2006) 100. [7] (a) D.A. Dougherty, Science 271 (1996) 163; (b) J.C. Ma, D.A. Dougherty, Chem. Rev. 97 (1997) 1303; (c) D.A. Dougherty, J. Nutr. 137 (2007) 1504S. [8] I.W. Wyman, D.H. Macartney, Org. Biomol. Chem. 8 (2010) 253. [9] (a) J.-M. Lehn, R. Meric, J.-P. Vigneron, M. Cesario, J. Guilhem, C. Pascard, Z. Asfari, J. Vicens, Supramol. Chem. 5 (1995) 97; (b) K.N. Koh, K. Araki, A. Ikeda, H. Otsuka, S. Shinkai, J. Am. Chem. Soc. 118 (1996) 755; (c) J.O. Magrans, A.R. Ortiz, M.A. Molins, P.H.P. Lebouille, J. Sánchez-Quesada, P. Prados, M. Pons, F. Gago, J.D. Mendoza, Angew. Chem. Int. Ed. Engl. 35 (1996) 1712. [10] (a) H.-J. Schneider, D. Güttes, U. Schneider, J. Am. Chem. Soc. 110 (1988) 6449; (b) M. Inoue, K. Hashimoto, K. Isagawa, J. Am. Chem. Soc. 116 (1994) 5517; (c) P. Ballester, A. Shivanyuk, A.R. Far, J. Rebek Jr., J. Am. Chem. Soc. 124 (2002) 14014; (d) S.-D. Tan, W.-H. Chen, A. Satake, B. Wang, Z.-L. Xu, Y. Kobuke, Org. Biomol. Chem. 2 (2004) 2719; (e) M. Demura, T. Yoshida, T. Hirokawa, Y. Kumaki, T. Aizawa, K. Nitta, I. Bitter, K. Tóth, Bioorg. Med. Chem. Lett. 15 (2005) 1367. [11] B. Schnatwinkel, M.V. Rekharsky, V.V. Borovkov, Y. Inoue, J. Mattay, Tetrahedron Lett. 50 (2009) 1374. [12] (a) J.O. Magrans, A.R. Oritiz, M.A. Molins, P.H.P. Lebouille, J. Sánchez-Quesada, P. Prados, M. Pons, F. Gago, J.D. Mendoza, Angew. Chem. Int. Ed. Engl. 35 (1996) 1712; (b) P. Ballestere, M.A. Sarmentero, Org. Lett. 8 (2006) 3477. [13] (a) K. Murayama, K. Aoki, Chem. Commun. (1997) 119; (b) K. Murayama, K. Aoki, Chem. Lett. (1998) 301; (c) I. Fujisawa, D. Takeuchi, R. Kato, K. Murayama, K. Aoki, Bull. Chem. Soc. Jpn. 84 (2011) 1133; (d) I. Fujisawa, D. Takeuchi, Y. Kitamura, R. Okamoto, K. Aoki, J. Phys.: Conf. Ser. 352 (2012) 12043;

[14]

[15]

[16]

[17] [18] [19] [20]

[21] [22] [23]

[24]

[25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [37]

193

(e) K. Aoki, K. Murayama, H. Nishiyama, J. Chem. Soc., Chem. Commun. (1995) 2221; (f) K. Murayama, K. Aoki, Chem. Commun. (1998) 607; (g) K. Aoki, T. Nagae, S. Yamaguchi, I. Fujisawa, Bull. Chem. Soc. Jpn. 78 (2005) 2066. (a) J.L. Atwood, L.J. Barbour, P.C. Junk, G.W. Orr, Supramol. Chem. 5 (1995) 105; (b) F. Perret, S. Guéret, O. Danylyuk, K. Suwinska, A.W. Coleman, J. Mol. Struct. 797 (2006) 1; (c) J.L. Atwood, A. Szumna, J. Supramol. Chem. 2 (2002) 479. (a) A. Shivanyuk, K. Rissanen, E. Kolehmainen, Chem. Commun. (2000) 1107; (b) A. Shivanyuk, J. Rebek Jr., Chem. Commun. (2001) 2374; (c) H. Mansikkamäki, M. Nissinen, C.A. Schalley, K. Rissanen, Chem. Commun. (2002) 1902; (d) M. Mäkinen, P. Vainiotalo, M. Nissinen, K. Rissanen, J. Am. Soc. Mass Spectrom. 14 (2003) 143; (e) H. Mansikkamäki, M. Nissinen, C.A. Schalley, K. Rissanen, New J. Chem. 27 (2003) 88; (f) H. Mansikkamäki, C.A. Schalley, M. Nissinen, K. Rissanen, New J. Chem. 29 (2005) 116; (g) H. Mansikkamäki, M. Nissinen, K. Rissanen, CrystEngComm 7 (2005) 519; (h) H. Mansikkamäki, M. Nissinen, K. Rissanen, Angew. Chem. Int. Ed. Engl. 43 (2004) 1243; (i) H. Mansikkamäki, S. Busi, M. Nissinen, A. Åhman, K. Rissanen, Chem. Eur. J. 12 (2006) 4289; (j) M. Luostarinen, Å. Ahman, M. Nissinen, K. Rissanen, Supramol. Chem. 16 (2004) 505. (a) L.R. MacGillivray, J.L. Atwood, Nature 389 (1997) 469; (b) S.J. Dalgarno, N.P. Power, J.L. Atwood, Coord. Chem. Rev. 252 (2008) 825; (c) P. Jin, S.J. Dalgarno, J.L. Atwood, Coord. Chem. Rev. 254 (2010) 1760. N.K. Beyeh, K. Rissanen, Isr. J. Chem. 51 (2011) 769. E.P. Kennedy, S.B. Weiss, J. Am. Chem. Soc. 77 (1955) 250. (a) J. Wittenberg, A. Kornberg, J. Biol. Chem. 202 (1953) 431; (b) E.P. Kennedy, S.B. Weiss, J. Biol. Chem. 222 (1956) 193. (a) D. Rachmilewitz, S. Eisenberg, Y. Stein, Biochim. Biophys. Acta 144 (1967) 624; (b) Y. Yamakawa, A. Ohsaka, J. Biochem. 81 (1977) 115; (c) M.G. Macfarlane, B.C.J.G. Knight, Biochem. J. 35 (1941) 884. (a) G. Blaser, J.M. Sanderson, M.R. Wilson, Org. Biomol. Chem. 7 (2009) 5119; (b) J.M. Sanderson, Org. Biomol. Chem. 5 (2007) 3276. M.E. Weber, E.K. Elliott, G.W. Gokel, Org. Biomol. Chem. 4 (2006) 83. (a) J. McAlister, D. Fries, M. Sundaralingam, ACS, Abstr. Papers (Summer) (1973) 197, taken from the CSD file (CSD code: PHSCHL).; (b) A. Fernandez-Botello, A. Escuer, X. Solans, M. Font-Bardia, A. Holy, H. Sigel, V. Moreno, Eur. J. Inorg. Chem. (2007) 1867. (a) M. Sundaralingam, L.H. Jensen, Science 150 (1965) 1035; (b) S. Abrahamsson, I. Pascher, Acta Crystallogr. 21 (1966) 79; (c) R.H. Pearson, I. Pascher, Nature 281 (1979) 499; (d) H. Hauser, I. Pascher, R.H. Pearson, S. Sundell, Biochim. Biophys. Acta 650 (1981) 21; (e) H. Hauser, I. Pascher, S. Sundell, J. Mol. Biol. 137 (1980) 249; (f) I. Pascher, S. Sundell, H. Eibl, K. Harlos, Chem. Phys. Lipids 39 (1986) 53; (g) I. Pascher, M. Lundmark, P.-G. Nyholm, S. Sundell, Biochim. Biophys. Acta 1113 (1992) 339; (h) I. Pascer, M. Lundmark, S. Sundell, H. Eibl, Progr. Coll. Polym. Sci. 108 (1998) 67; (i) V.S. Fundamensky, I.I. Bannova, V.D. Franke, V.A. Karasev, N.A. Korovnikova, V.V. Luchinin, Membr. Cell Biol. 11 (1997) 137; (j) V.A. Karasev, V.S. Fundamensky, I.I. Bannova, V.D. Franke, V.E. Stefanov, Biochim. Biophys. Acta 1466 (2000) 23; (k) D.S. Moss, W.V. Robinson, J. Cryst. Mol. Struct. 6 (1976) 317. Y. Aoyama, Y. Tanaka, S. Sugahara, J. Am. Chem. Soc. 111 (1989) 5397. ‘‘CrystalClear: An integrated program for the collection and processing of area detector data’’, Rigaku Corporation, 1997. G.M. Sheldrick, Acta Crystallogr. A64 (2008) 112. C. Kabuto, S. Akine, T. Nemoto, E. Kwon, J. Cryst. Soc. Jpn. 51 (2009) 218. (a) M. Sundaralingam, Ann. N.Y. Acad. Sci. U.S.A. 195 (1972) 324; (b) M. Sundaralingam, Nature 217 (1968) 35. C. Chothia, P. Pauling, Nature 219 (1968) 1157. A.B. Barrett, G.C.K. Roberts, A.S.V. Burgen, G.M. Clore, Mol. Pharmacol. 24 (1983) 443. (a) S. Tsuzuki, T. Uchimaru, M. Mikami, J. Phys. Chem. A 107 (2003) 10414; (b) A.S. Reddy, H. Zipse, G.N. Sastry, J. Phys. Chem. B 111 (2007) 11546. R. Hilgenfeld, W. Saenger, Top. Curr. Chem. 101 (1982) 1. Y. Su, S.-Q. Zang, C.-L. Ni, Y.-Z. Li, Q.-J. Meng, J. Inorg. Chem. 20 (2004) 845. B.K. Toeplitz, A.I. Cohen, P.T. Funke, W.L. Parker, J.Z. Gougoutas, J. Am. Chem. Soc. 101 (1979) 3344. J. Burgess, E. Raver, Adv. Inorg. Chem. 61 (2009) 251. (a) B.-Y. Kwak, Y.-M. Zhang, M. Yun, R.J. Heath, C.O. Rock, S. Jackowski, H.-W. Park, J. Biol. Chem. 277 (2002) 4343; (b) J. Lee, J. Johnson, Z. Ding, M. Paetzel, R.B. Cornell, J. Biol. Chem. 284 (2009) 33535.