Conformation and anion binding properties of cyclic hexapeptides containing l -4-hydroxyproline and 6-aminopicolinic acid subunits

Abstract

Two cyclic hexapeptides containing alternating all R and all S configured L-(4R͞S)-hydroxyproline and 6-aminopicolinic acid subunits are presented, and the influence of the hydroxyl groups on the solubility, conformation, and receptor properties is investigated. Cyclopeptide 2, containing the natural 4R configured hydroxyproline, adopts a conformation similar to that of the unsubstituted peptide 1, which is able to bind anions such as halides and sulfate in aqueous solution. 2 also interacts with these anions, but whereas 1 forms sandwich type 2:1 complexes, in which the anion is bound by two cyclopeptide moieties, 2 forms 1:1 complexes. The stabilities of the halide and sulfate complexes of 2 range between 10 0 and 10 2 M ؊1 in 80% D2O͞CD3OD. Complex formation is detectable even in water, but with slightly smaller stability constants. Using this information a quantitative evaluation of the stability of the 2:1 complexes of 1, for which overall stability constants in the order 10 4 to 10 5 M ؊2 in 80% D2O͞CD3OD were observed, was made. In contrast to 2, the conformation of 3, containing the non-natural 4S configured hydroxyproline, is strongly affected by the presence of the hydroxyl groups. In d 6-DMSO and methanol͞water mixtures a slow conformational equilibrium between two C3-symmetrical conformers is observed, and 3 is thus much less preorganized for anion binding than either 1 or 2.T he crystal structures of anion binding proteins with the substrate resting in the active site have provided valuable information on the principles nature uses for the recognition of negatively charged compounds (1). Important binding interactions are, for example, multiple hydrogen bonds formed between the substrate and NH groups of the protein backbone or hydrogen bond donors in amino acid side chains (2, 3). A way of mimicking these interactions in an artificial system is to arrange amide or urea NH groups around the cavity of a suitable host molecule. This strategy has led to the development of many artificial hosts for anions, some of which possess remarkable substrate affinity, even in highly competitive solvents such as DMSO or acetonitrile (4-12). The ultimate goal has, of course, been the design of receptors that bind anions by hydrogen bonds in water. However, despite the recent advances in the development of anion receptors (4-7), most systems described so far require strong electrostatic or coordinative interactions to be effective in this solvent. One of the few exceptions is the cyclic hexapeptide 1 that has recently been described by us (13). This neutral macrocyclic receptor interacts with anions such as halides or sulfate even in water͞methanol mixtures, a behavior that can largely be attributed to the special geometry of the complexes formed. We have found that the presence of a suitable anion in solution induces an aggregation of two cyclopeptide molecules, whereby a cavity is formed into which the anion is included (Fig. 1). In this complex, the anion is shielded from the surrounding solvent and can thus inte...

Advances in Anion Supramolecular Chemistry: From Recognition to Chemical Applications

“…Furthermore, one of the macrocycles was able to bind sulfate in pure D 2 O, admittedly with a modest association constant (K a = 56 m À1 ). [56] In subsequent work, covalently linking two cyclopeptides with adipic acid allowed for "molecular oyster" receptors able to bind sulfate with log K a % 5 in a 50:50 mixture of H 2 O and CH 3 OH (Figure 12 b). [57] The ability of these receptors to operate in such competitive solvent media has been accredited to hydrophobic interactions between the two cyclopeptide rings that encapsulate the bound anion.…”

Chiral hemicucurbit[8]uril as an anion receptor: selectivity to size, shape and charge distribution

“…10,11 This led to the design of sandwich-like bis(cyclopeptide) receptors that reached association constants of up to 10 6 M –1 for binding SO 4 2– in a water–methanol mixture. 12,13 Employing a hydrophobic pocket for anion binding in water has been illustrated by the Gibb's octa-acid cavitand, 14 where the binding of partially hydrated anions yielded association constants up to 10 3 M –1 at pH 11.5.…”

Anion recognition by cyclic peptides

“…In contrast to 18, 19a and 19b form 1 : 1 complexes with anions with moderate binding affinities in the range of 1 to 100 M À1 in 80% D 2 O-CD 3 OD. 48 In a subsequent report receptor 20, in which two cyclopeptide units are covalently linked with an adipinic acid spacer, stabilises the sandwich-type complexes with halides, sulfate and nitrate, which now exhibit 1 : 1 binding stoichiometry (Fig. 3).…”