Philjae Kang

Structural Characterization of α/β‐Peptides having Alternating Residues: X‐ray Structures of the 11/9‐Helix from Crystals of Racemic Mixtures

The development of proteinlike structures of oligomers which contain unnatural amino acids (peptidic foldamers) is an active area of research. A variety of distinct conformations of peptidic foldamers that are analogous to protein secondary structures have been discovered to date. Helical structures of peptidic foldamers are particularly interesting because diverse helical conformations with unconventional hydrogen-bonding interactions are available. Two prominent helices, the a-helix and the 310-helix, in natural proteins arise from (i,i + 4) and (i,i + 3) C=O···H N hydrogen bonding, respectively. A number of helical structures in peptidic foldamers arise from a single type of C=O···H N hydrogen bond, thus resulting in a macrodipole along the helical axis. In contrast, there are unique helical structures of peptidic foldamers and they feature the alternation of two hydrogenbonding types with opposite directions along the helical axis (mixed helices). Mixed helices give rise to relatively small macrodipoles because of the alternation of hydrogen-bonding directions. Since Seebach and co-workers reported the bpeptide 12/10-helix that arises from alternating (i,i 1) and (i,i + 3) hydrogen bonds, a number of mixed helices have been reported for diverse unnatural peptide backbones, such as b-peptides, a/b-peptides, and a/g-peptides. The 11/9helix, one of mixed helices for a/b-peptides, contains two types of intramolecular hydrogen bonds: an 11-atom ring hydrogen bond between the C=O of b-residue(i) and the H-N of a-residue(i+3), and a 9-atom ring hydrogen bond between the C=O of a-residue(i) and the H-N of b-residue(i 1). Among the a/b-peptide helices with alternating residue types, the 11/9-helix has been predicted to be most stable, by theoretical calculations, both in vacuum and in solution. A couple of 11/9-helical a/b-peptide backbones have been characterized by two-dimensional NMR experiments. However, the application of this unique helical peptide backbone is limited because detailed structural information for the 11/9-helix, which is derived from high-resolution structures, is not available to date. There are crystal structures of aba-tripeptides that display 11and 9-atom ring hydrogen bonds. It is still insufficient to derive structural parameters for the 11/9-helix from these trimer structures because one helical turn is defined by at least four points. It is thus desirable to obtain the crystal structures of 11/9-helical a/bpeptides containing four residues or more. Herein we report crystal structures of the a/b-peptide 11/9-helix with multiple helical turns, which allowed us to derive the structural parameters for the 11/9-helix. We hypothesized that the conformational preference of cis-2-aminocyclohexanecarboxylic acid (cis-ACHC) is amenable to the 11/9-helix in light of the local conformations of cis-ACHC in the crystal state, as reported previously. In addition, oligomers of cis-ACHCs with alternating chiralities display 12/10-helical conformations in solution, and are homologous to the 11/9-helix in a/ b-peptides. We chose (1R,2S)-2-aminocyclohexanecarboxylic acid and d-alanine to prepare a series of a/b-peptide oligomers. NOESY or ROESY spectra for the a/b-peptides 1–3 are consistent with the characteristic NOEs for the 11/9helix, that is, a-residue CaH(i)–a-residue NH(i+2) and bresidue NH(i)–a-residue NH(i+1) as reported by Sharma and co-workers (Figure 1). All but one of these characteristic NOEs were observed for 1–3. Only the NOE between the bresidue NH(2) and a-residue NH(3) was not observed for the trimer 1.

Folding-Generated Molecular Tubes Containing One-Dimensional Water Chains.

A series of indolocarbazole-pyridine (IP) oligomers were prepared that fold into helical conformations, and their folding features in solution and in the solid state were revealed. Helical folding of these IP foldamers is induced by dipolar interactions through the ethynyl bond and π-stacking between two repeating units. Upon helical folding, (1)H NMR signals of aromatic protons were significantly shifted upfield by Δδ = 0.5-2.2 ppm. In addition, hypochromic shifts and fluorescence quenching were observed in the absorption and emission spectra. X-ray crystal structures clearly demonstrated that IP foldamers folded to helical structures with cylindrical internal cavities wherein 3 or 5 water molecules were occupied by hydrogen-bonding interactions in a 1-D array, reminiscent of transmembrane water channels, called aquaporins.

A helically twisted imine macrocycle that allows for determining the absolute configuration of α-amino carboxylates

Binding of α-amino carboxylates to a helically twisted imine macrocycle based on the indolocarbazole scaffold gives rise to characteristic circular dichroism spectra, and the patterns of the Cotton effects are consistent with the absolute configuration of α-amino carboxylates.

Synthetic K⁺/Cl⁻-selective symporter across a phospholipid membrane.

Synthetic molecules which selectively transport sodium or potassium chloride across a lipid membrane have been prepared. The salt carriers consist of two heteroditopic binding sites, an anion-binding cavity with three hydrogen bond donors and an azacrown ether for binding an alkali metal cation. The association constants between the carriers and chloride ion have been enhanced by 1 order of the magnitude in the presence of sodium or potassium ion in 10% (v/v) CD3OH/CD3CN, due to the formation of a contact ion-pair between the bound cation and chloride as demonstrated by the single-crystal X-ray structure of a sodium chloride complex. A series of transport experiments have demonstrated that the synthetic molecule functions as a mobile carrier of transporting salts via M(+)/Cl(-) symport. Among alkali metal chlorides, the carrier with an 18-azacrown-6 exhibits a strong selectivity toward potassium chloride, while the carrier with a 15-azacrown-5 displays a moderate selectivity for sodium chloride.

Helical folding of α/β-peptides containing β-amino acids with an eight-membered ring constraint

αβα-Tripeptide that contains a cyclic β-amino acid with an eight-membered ring, a cis-2-aminocyclooct-5-enecarboxylic acid (cis-ACOE) or a cis-2-aminocyclooctanecarboxylic acid (cis-ACOC) displayed an 11/9-helical turn in the crystal state. The related α/β-peptide oligomers were shown to adopt 11/9-helical conformations in solution.

Helical Aromatic Foldamers Functioning as a Fluorescence Turn-on Probe for Anions

Indolocarbazole-pyridine hybrid foldamers are strongly fluorescent in an extended random conformation, but the fluorescence is completely quenched upon folding to a helical conformation due to the compact stacking between aryl planes in the backbone. Anion binding disturbs the helical conformation, thus regenerating the fluorescence of the foldamers. This unique property has been utilized to develop a fluorescence turn-on probe for anions such as sulfate and fluoride.

Synthesis of cobalt cluster-based supramolecular triple-stranded helicates

A cobalt cluster-based triple-stranded helicate, Co8(PDA)6(PTA)3(DMF)3(H2O)3 () (PDA = 2,6-pyridinedicarboxylate, PTA = benzene-1,3-dicarboxylate, DMF = dimethylformamide) was successfully synthesized and fully characterized. Complex can be used as a supramolecular building block in constructing a higher-order helix-of-helix structure, [Co8(PDA)6(PTA)3(DMF)2(H2O)4-0.51(Co(OHn)2)] (n = 1 or 2) ().

A Cobalt Supramolecular Triple-Stranded Helicate-based Discrete Molecular Cage

We report a strategy to achieve a discrete cage molecule featuring a high level of structural hierarchy through a multiple-assembly process. A cobalt (Co) supramolecular triple-stranded helicate (Co-TSH)-based discrete molecular cage (1) is successfully synthesized and fully characterized. The solid-state structure of 1 shows that it is composed of six triple-stranded helicates interconnected by four linking cobalt species. This is an unusual example of a highly symmetric cage architecture resulting from the coordination-driven assembly of metallosupramolecular modules. The molecular cage 1 shows much higher CO2 uptake properties and selectivity compared with the separate supramolecular modules (Co-TSH, complex 2) and other molecular platforms.

Stabilization of 11/9-helical α/β-peptide foldamers in protic solvents

α/β-Peptides with alternating α-amino acid and cis-2-aminocyclohexanecarboxylic acid (cis-ACHC) residues adopt 11/9-helical conformations, the folding propensity of which decreases as the solvent polarity increases. We report a new cis-ACHC analogue, cis-2-amino-cis-4-methylcyclohexanecarboxylic acid, which significantly stabilizes the 11/9-helix propensity in protic solvents.

cis-2-Aminocyclohex-4-enecarboxylic acid as a new building block of helical foldamers

cis-2-Aminocyclohex-4-enecarboxylic acid (cis-ACHE) is a conformationally constrained β-amino acid. We showed that the conformational preference of a cis-ACHE residue is similar to that of cis-2-aminocyclohexanecarboxylic acid. α/β-Peptides that consist of the alternation of (1S,2R)-cis-ACHE and L-alanine adopted 11/9-helical conformations in solution and in the crystal state.