This trifluoromethyl zipper arrangement is reminiscent of the leucine zippers 16 that stabilize coiled coils in water-soluble proteins, as well as the alanine coils found frequently in membrane proteins 17. Arylamides that lie along the edges of neighbouring hexagons interact in what we term a ‘trifluoromethyl zipper’ interaction, in which the water-repelling trifluoromethyl groups intimately interdigitate along a non-exact twofold axis of symmetry. Each arylamide engages in two distinct types of interactions, which together uniquely define and stabilize the overall assembly. The 48 triarylamides lie with their backbones roughly parallel to the edges of the eight hexagons ( Fig. Each arylamide dimer associates with 113 water molecules, which are primarily located within the cores of the truncated octahedra, for a total of 2,712 water molecules per unit cell. The unit cell ( Figs 2 and 3) contains 24 copies of the asymmetric dimer, arranged in the shape of an omnitruncated octahedron, a special case of an Archimedean solid, the truncated octahedron, which has eight hexagonal and six square faces. The arylamide crystallizes in a space group of high symmetry, P 3 n, which has not yet been seen for an organic framework structure. A complex assembly stabilized by diverse interactions It is unlikely that the metal ion plays a significant role in the biological activity of the molecule, because other variants of this triarylamide that lack the thioether and/or the ethylamine-ligating groups have high antimicrobial activity 7, 11. The overall arrangement is consistent with that determined by solid-state NMR of the triarylamide bound to phospholipid bilayers in the absence of Cd 2+ (ref. The trifluoromethyl groups and the nonpolar portions of the aryl backbone segregate from the strongly polar amine and guanidine side chains. The structure of the triarylamide monomer in the crystallographic lattice displays the amphiphilic structure anticipated in the design. Thus, the metal ions appear to promote crystallization, not by bridging between sites as in assembly systems formed between polycoordinate metal ions and polydentate ligands 14, but rather by subtly changing the physical and geometric properties of the molecule. However there are no ligand–metal ion interactions between sites within a single molecule or between molecules in the crystal lattice. The neighbouring aminoethyl group serves as a fourth ligand, and acetates or (in one case) a water molecule complete the ligand environment. Each Cd 2+ interacts with the pyrimidyl nitrogen and thioether, replacing the hydrogen-bonded interactions used in the original design with metal–ligand interactions. The foldamers also interact weakly with Cd 2+ in aqueous solution ( Supplementary Fig. In the crystal, Cd 2+ ions displace the arylamide protons on the amide units connecting the phenyl and pyrimidyl rings. Each monomer shows the expected amphiphilic structure, but the arylamide backbone is stabilized differently in the presence than in the absence of Cd 2+ (ref. Two monomers with closely related structures form the asymmetric unit ( Fig. To obtain a high-resolution structure of 1, it was crystallized from aqueous solution by the hanging-drop method in the presence of 0.05 M cadmium sulphate and sodium acetate (1.0 M). Nuclear magnetic resonance (NMR) studies showed that the triarylamide assembled into a higher order oligomer in aqueous solution ( Supplementary Figs 1 and 2). The assembly can be understood in terms of physicochemical principles, including the hydrophobic effect, aromatic stacking, hydrogen bonding, and ion-binding and could advance the nanoscale engineering of complex molecular assemblies.Ĭrystal structure of 1 shows the designed amphiphilicity More importantly, the foldamer, which was crystallized from aqueous solution in the absence of membranes, associates to form a honeycomb geometry with each cubicle as a truncated octahedron. Here we show the crystallographic structure of 1 and confirm its amphiphilic structure, which is required for binding to bilayers. Together, these groups create a facially amphiphilic, positively charged structure, previously shown to be essential for their high antibacterial activity in vitro and in animal models 12. Pendant thioether substituents within the diaminobenzene units help to rigidify the structure and also provide points of attachment for positively charged aminoethyl side chains. It is a triarylamide comprising two 1,3-diaminobenzene units linked by a 4,6-dicarboxy-substituted pyrimidine and two terminal guanidine-containing amides. Compound 1 was originally designed as a mimic of antimicrobial peptides 12.
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