A hydrogen-bonding-modulated molecular rotor: environmental effect in the conformational stability of peptidomimetic macrocyclic cyclophanes

The conformational behavior of 16- to 18-membered ring peptidomimetic p-cyclophanes 1a,b-3a,b has been studied by NMR. The cycles bearing 16 and 17 atoms showed a dynamic process within the NMR time scale, produced by the rotation of the aromatic p-diphenylene moiety with respect to the macrocyclic main plane. The temperature dependence of 1H NMR spectra has been studied in order to get activation parameters of the energetic barrier for the process (VT-NMR and line shape analysis). The rate of the movement clearly depends on the macrocyclic ring size and the nature of the peptidomimetic side chain. Entropic and enthalpic contributions to the free energy of activation are discussed. The rotation of the aromatic ring is closely related to the intramolecular hydrogen bonding pattern, as suggested by temperature factors of NH chemical shifts (DeltadeltaNH/DeltaT) and molecular modeling. The interconnected roles of the solvation and the intramolecular H-bonds have been established by measurements (VT-NMR and DeltadeltaNH/DeltaT) in environments of different polarities and H-bonding abilities. We concluded that the conformational stability of the systems directly depends on the stability of the intramolecular H-bonding pattern. We finally showed how one of these peptidomimetics behaves as a methanol-dependent artificial molecular rotor. In this simple molecular device, the well-defined molecular rotation is tuned by the competition between intramolecular hydrogen bonds and interactions with the solvent.     

Intrinsic conformational characteristics of alpha,alpha-diphenylglycine

Quantum mechanical calculations at the B3LYP/6-31+G(d,p) level have been used to investigate the intrinsic conformational preferences of alpha,alpha-diphenylglycine, a simple alpha,alpha-dialkylated amino acid bearing two phenyl substituents on the alpha-carbon, in both the gas phase and aqueous solution. Nine minimum energy conformations have been characterized for the N-acetyl-N'-methylamide derivative within a relative energy range of about 9 kcal/mol. The relative stability of these structures is largely influenced by specific backbone...side chain and side chain...side chain interactions that can be attractive (N-H...pi and C-H...pi) or repulsive (C=O...pi). On the other hand, comparison with the minimum energy conformations calculated for alpha-aminoisobutyric acid, in which the two phenyl substituents are replaced by methyl groups, revealed that the bulky aromatic rings of alpha,alpha-diphenylglycine induce strain in the internal geometry of the peptide. Finally, a set of force-field parameters for classical Molecular Mechanics calculations was developed for the investigated amino acid. Molecular Dynamics simulations in aqueous solutions have been carried out to validate the parameters obtained.     

Highly selective recognition of diols by a self-regulating fine-tunable methylazacalix[4]pyridine cavity: guest-dependent formation of molecular-sandwich and molecular-capsule complexes in solution and the solid state

The molecular recognition of methylazacalix[4]pyridine (MACP-4; 1) towards various diols was investigated by using (1)H NMR spectroscopic and X-ray diffraction analysis. As a unique macrocyclic host molecule that undergoes conformational inversions very rapidly in solution, MACP-4 has been shown to self-regulate its conformation, through the formation of different conjugations of the four bridging nitrogen atoms with their adjacent pyridine rings, to form a cavity that best fits the guest species through intermolecular hydrogen-bond, C-H...pi, and pi-pi interactions between the host and guest. As a consequence, depending upon the diol structure and geometry, MACP-4 forms a 1:1 molecular sandwich, 2:1 molecular capsule, and 1:2 butterfly-layered complex with the guests. As a result of favorable enthalpy and entropy effects, MACP-4 exhibits excellent selectivity in the recognition of resorcinol, thus resulting in a very stable 1:1 sandwich complex with resorcinol with a binding constant of 6000 (M-1). The dynamic (1)H NMR spectroscopic study demonstrated that the 1,3-alternate conformation of the macrocyclic ring of the MACP-4resorcinol complex (13) is stable at low temperature (T<243 K), and its conformational inversion requires a larger activation energy (DeltaG++=(45.5+/-2.2) kJ mol(-1)). In the presence of an excess amount of resorcinol, however, the conformational inversion of the MACP-4resorcinol complex proceeds more readily with a decreased activation energy (DeltaG++=(33.5+/-1.5) kJ mol(-1)) owing most probably to the favorable enthalpy effect of the [3...1...3]++transition state.     

Structural and co-conformational effects of alkyne-derived subunits in charged donor-acceptor [2]catenanes

Four donor-acceptor [2]catenanes with cyclobis(paraquat-p-phenylene) (CBPQT4+) as the pi-electron-accepting cyclophane and 1,5-dioxynaphthalene (DNP)-containing macrocyclic polyethers as pi-electron donor rings have been synthesized under mild conditions, employing Cu+-catalyzed Huisgen 1,3-dipolar cycloaddition and Cu2+-mediated Eglinton coupling in the final steps of their syntheses. Oligoether chains carrying terminal alkynes or azides were used as the key structural features in template-directed cyclizations of [2]pseudorotaxanes to give the [2]catenanes. Both reactions proceed well with precursors of appropriate oligoether chain lengths but fail when there are only three oxygen atoms in the oligoether chains between the DNP units and the reactive functional groups. The solid-state structures of the donor-acceptor [2]catenanes confirm their mechanically interlocked nature, stabilized by [pi...pi], [C-H...pi], and [C-H...Omicron] interactions, and point to secondary noncovalent contacts between 1,3-butadiyne and 1,2,3-triazole subunits and one of the bipyridinum units of the CBPQT4+ ring. These contacts are characterized by the roughly parallel orientation of the inner bipyridinium ring system and the 1,2,3-triazole and 1,3-butadiyne units, as well as by the short [pi...pi] distances of 3.50 and 3.60 A, respectively. Variable-temperature 1H NMR spectroscopy has been used to identify and quantify the barriers to the conformationally and co-conformationally dynamic processes. The former include the rotations of the phenylene and the bipyridinium ring systems around their substituent axes, whereas the latter are confined to the circumrotation of the CBPQT4+ ring around the DNP binding site. The barriers for the three processes were found to be successively 14.4, 14.5-17.5, and 13.1-15.8 kcal mol-1. Within the limitations of the small dataset investigated, emergent trends in the barrier heights can be recognized: the values decrease with the increasing size of the pi-electron-donating macrocycle and tend to be lower in the sterically less encumbered series of [2]catenanes containing the 1,3-butadiyne moiety.     

Evidence for homo-conjugation between two revolving 14pi-electron systems in 10b-methyl-10c-[2-(10b,10c-dimethyl-10b,10c-dihydropyrenyl)]-10b,10c-dihydropyrene

Ring contraction followed by an elimination reaction on anti-9-methyl-18-trans-2-(10b,10c-dimethyl-10b,10c-dihydropyrenyl)-2,11-dithia[3,3]metacyclophane gave the desired compound 10b-methyl-10c-[2-(10b,10c-dimethyl-10b,10c-dihydropyrenyl)]-10b,10c-dihydropyrene. 1H NMR spectroscopic analysis indicated a ring current effect over a considerable distance from the macro-molecular plane of each of the aromatic rings with the two pi systems freely rotating. Bathochromic shifts and peak broadening in its electronic spectrum clearly supports the presence of through-space pi-pi interactions between the two aromatic rings. This should serve as a good model to verify homo-conjugation effect in such a novel system where the two pi systems are freely revolving.     

Synthesis of amidocrownophanes with 27‐ and 28‐membered rings and their molecular recognition toward urea and its derivatives

Novel crownophanes with 27‐ and 28‐membered rings having two hydroxyl groups, two amide groups, and aromatic moieties such as naphthalene, pyridine, and phenyl rings were successfully synthesized by a one‐step reaction from the corresponding macrocyclic polyethers via “tandem Claisen rearrengement” in moderate yields. They can solubilize urea and its derivatives into chloroform solution, while the corresponding macrocyclic polyethers do not solubilize them. According to NMR studies, crownophanes 1 and 2 interact with urea and its derivatives forming 1:1 complexes.     

Multiple interactions in the self-association of porphyrin discotic mesogens

The conformational preferences and the self-associational behaviors of two hemin-derived porphyrin compounds, a tetramethyl ester and a liquid crystalline tetrakis(3,5-didodecyloxyphenyl)ester, have been studied by UV/vis and (1)H NMR spectroscopy in solution. Results indicate that the 3,5-didodecyloxyphenyl units play an important role in both the conformational and the self-associational behaviors of the mesomorphic tetraester. In the monomeric, nonassociated species, the two propionic 3,5-didodecyloxyphenyl esters establish mutual CH/pi interactions that restrict the fluctuative behavior of the chains. In the dimeric, self-associated species, intermolecular CH/pi interactions occur in addition to the pi-pi stacking of the porphyrin cores. The temperature-dependent addition of side CH/pi interactions to the pi-pi stacking of the porphyrin rings accounts for the observed tightening and for the slower dynamics of the dimeric structure. The relationship between the self-associational behavior and the mesomorphism of the hemin-derived porphyrin tetraesters is also discussed.     

1H and 13C NMR studies of some aromatic dilactones (precursors of paracyclophanes)

Carbon-13 and proton NMR data of macrocyclic diaromatic dilactones are presented. The observed behaviour of the spectra as a function of temperature shows that the energy barrier for the re-orientation of the side chains is lower than 49 kJ mol^?1 (12 kcal mol^?1) and that the energy barrier for the rotation of the aromatic rings is larger than 99 kJ mol^?1 (24 kcal mol^?1). Hence, chiral substituted dilactones of this type will be resolvable, and the enantiomers can be easily handled at room temperature.     

Tryptophan side chain electrostatic interactions determine edge-to-face vs parallel-displaced tryptophan side chain geometries in the designed beta-hairpin "trpzip2"

The interaction geometries of the four tryptophan (Trp) side chains in the 12-residue designed beta-hairpin trpzip2 are investigated using all-atom explicit-solvent molecular dynamics simulations. The experimentally observed edge-to-face (EtF) pairwise interaction geometries are stable on a time scale of 10 ns. However, removing the electrostatic multipoles of the Trp side chains while retaining the dipoles of the side chains' NH moieties induces a conformational change to a geometry in which three of the four side chains interact in a parallel-displaced (PD) manner. Free energy simulations of the Etf to PD conformational change reveal that, with the side chain multipole moments intact (+MP), the EtF conformation is preferred by 5.79 kcal/mol. Conversely, with only the dipole moments of the side chain NH moieties intact (-MP), the PD conformation's free energy is more favorable by 1.71 kcal/mol. In contrast to energetic similarities for Trp side chain-water electrostatic and Trp side chain-Trp side chain and Trp side chain-water van der Waals, +MP Trp side chain-Trp side chain electrostatic interactions are more favorable by 4.21 kcal/mol in the EtF conformation, while in the -MP case the EtF and PD conformations' Trp side chain-Trp side chain electrostatic energies are nearly identical. The results highlight the importance of electrostatic multipole moments in determining aromatic-aromatic interaction geometries in aqueous biomolecular systems and argue for the inclusion of this physics in simplified models used for protein-ligand docking and protein structure prediction, possibly through a truncated Coulomb term between aromatic moieties.     

Chemical modulation of peptoids: synthesis and conformational studies on partially constrained derivatives

The high conformational flexibility of peptoids can generate problems in biomolecular selectivity as a result of undesired off-target interactions. This drawback can be counterbalanced by restricting the original flexibility to a certain extent, thus leading to new peptidomimetics. By starting from the structure of an active peptoid as an apoptosis inhibitor, we designed two families of peptidomimetics that bear either 7-substituted perhydro-1,4-diazepine-2,5-dione 2 or 3-substituted 1,4-piperazine-2,5-dione 3 moieties. We report an efficient, solid-phase-based synthesis for both peptidomimetic families 2 and 3 from a common intermediate. An NMR spectroscopic study of 2a,b and 3a,b showed two species in solution in different solvents that interconvert slowly on the NMR timescale. The cis/trans isomerization around the exocyclic tertiary amide bond is responsible for this conformational behavior. The cis isomers are more favored in nonpolar environments, and this preference is higher for the six-membered-ring derivative 3a,b. We propose that the hydrogen-bonding pattern could play an important role in the cis/trans equilibrium process. These hydrogen bonds were characterized in solution, in the solid state (i.e., by using X-ray studies), and by molecular modeling of simplified systems. A comparative study of a model peptoid 10 containing the isolated tertiary amide bond under study outlined the importance of the heterocyclic moiety for the prevalence of the cis configuration in 2a and 3a. The kinetics of the cis/trans interconversion in 2a, 3a, and 10 was also studied by variable-temperature NMR spectroscopic analysis. The full line-shape analysis of the NMR spectra of 10 revealed negligible entropic contribution to the energetic barrier in this conformational process. A theoretical analysis of 10 supported the results observed by NMR spectroscopic analysis. Overall, these results are relevant for the study of the peptidomimetic/biological-target interactions.     

Dual-mode "co-conformational" switching in catenanes incorporating bipyridinium and dialkylammonium recognition sites

Three [2]catenanes and three [3]catenanes incorporating one or two pi-electron-rich macrocyclic polyethers and one pi-electron-deficient polycationic cyclophane have been synthesized in yields ranging from 4 to 38%. The pi-electron-rich macrocyclic components possess either two 1,4-dioxybenzene or two 1.5-dioxynaphthalene recognition sites. The pi-electron-deficient cyclophane components incorporate two bipyridinium and either one or two dialkylammonium recognition sites. The template-directed syntheses of these catenanes rely on i) pi...pi stacking interactions between the dioxyarene and bipyridinium recognition sites, ii) C-H...O hydrogen bonds between some of the bipyridinium hydrogen atoms and some of the polyether oxygen atoms, and iii) C-H...pi interactions between some of the dioxyarene hydrogen atoms and the aromatic spacers separating the bipyridinium units. The six catenanes were characterized by mass spectrometry and by both 1H and 13C NMR spectroscopy. The absorption spectra and the electrochemical properties of the catenanes have been investigated and compared with those exhibited by the component macrocycles and by related known catenanes. Broad and weak absorption bands in the visible region, originating from charge-transfer (CT) interactions between electron-donor and electron-acceptor units, have been observed. Such charge-transfer interactions are responsible for the quenching of the potentially fluorescent excited states of the aromatic units of the macrocyclic polyether components. The redox behavior of these novel compounds has been investigated and correlations among the observed redox potentials are illustrated and discussed. The catenanes undergo co-conformational switching upon one-electron reduction of the two bipyridinium units. One of them--in its reduced form--can be also switched by acid/base inputs and exhibits AND logic behavior. The co-conformational rearrangements induced by the redox and acid/base stimulations lend themselves to exploitation in the development of molecular-level machines and logic gates.     

Macrocyclic β-Sheets Stabilized by Hydrogen Bond Surrogates

Mimics of protein secondary and tertiary structure offer rationally-designed inhibitors of biomolecular interactions. β-Sheet mimics have a storied history in bioorganic chemistry and are typically designed with synthetic or natural turn segments. We hypothesized that replacement of terminal inter-β-strand hydrogen bonds with hydrogen bond surrogates (HBS) may lead to conformationally-defined macrocyclic β-sheets without the requirement for natural or synthetic β-turns, thereby providing a minimal mimic of a protein β-sheet. To access turn-less antiparallel β-sheet mimics, we developed a facile solid phase synthesis protocol. We surveyed a dataset of protein β-sheets for naturally observed interstrand side chain interactions. This bioinformatics survey highlighted an over-abundance of aromatic–aromatic, cation-π and ionic interactions in β-sheets. In correspondence with natural β-sheets, we find that minimal HBS mimics show robust β-sheet formation when specific amino acid residue pairings are incorporated. In isolated β-sheets, aromatic interactions endow superior conformational stability over ionic or cation-π interactions. Circular dichroism and NMR spectroscopies, along with high-resolution X-ray crystallography, support our design principles.     

Helical aromatic oligoamides: reliable, readily predictable folding from the combination of rigidified structural motifs

Factors responsible for the folding of aromatic oligoamides with backbones rigidified by local three-center H-bonds were investigated. The stability of the three-center H-bonds was quantified by the half-lives of amide proton-deuterium exchange reactions, which show that the three-center H-bonds were largely intact at room temperature in the oligomer examined. This result is consistent with our current and previous 2D NMR studies. The overall helical conformation of nonamer 1 was found by variable-temperature NOESY studies to be dynamic. As temperature rose, the end-to-end NOEs rapidly disappeared, while the amide side chain NOEs were still readily detectable, corresponding to the "breath" and stretching of the helix by slightly twisting the local H-bonded rings. Based on the simple repetition of the same structural motif and local conformational preference, undecamer 2 was found to fold into well-defined helical conformation. The predictability of the folding of these backbone-rigidified aromatic oligoamides was demonstrated by a simple modeling method using structural parameters from oligomers with known crystal structures. The reliability and generality of the modeling methods were shown by the excellent agreement between the modeled structures corresponding to 1 and 2 and data from NOESY studies.     

Investigation of aromatic-backbone amide interactions in the model peptide acetyl-Phe-Gly-Gly-N-methyl amide using molecular dynamics simulations and protein database search.

Weakly polar interactions between the side-chain aromatic rings and hydrogens of backbone amides (Ar-HN) are found in unique conformational regions. To characterize these conformational regions and to elucidate factors that determine the conformation of the Ar-HN interactions, four 4-ns molecular dynamics simulations were performed using four different low-energy conformations obtained from simulated annealing and one extended conformation of the model tripeptide Ac-Phe-Gly-Gly-NH-CH(3) as starting structures. The Ar(i)-HN(i+1) interactions were 4 times more frequent than were Ar(i)-HN(i+2) interactions. Half of the conformations with Ar(i)-HN(i+2) interactions also contained an Ar(i)-HN(i+1) interaction. The solvent access surface area of the Phe side chain and of the amide groups of Phe1, Gly2, and Gly3 involved in Ar-HN interactions was significantly smaller than in residues not involved in such interactions. The number of hydrogen bonds between the solvent and Phe1, Gly2, and Gly3 amide groups was also lower in conformations with Ar-HN interactions. For each trajectory, structures that contained Ar(i)-HN(i), Ar(i)-HN(i+1), and Ar(i)-HN(i+2) interactions were clustered on the basis of similarity of selected torsion angles. Attraction energies between the aromatic ring and the backbone amide in representative conformations of the clusters ranged from -1.98 to -9.24 kJ mol(-1) when an Ar-HN interaction was present. The most representative conformations from the largest clusters matched well with the conformations from the Protein Data Bank of Phe-Gly-Gly protein fragments containing Ar-HN interactions.     

Cation [M = H+, Li+, Na+, K+, Ca2+, Mg2+, NH4+, and NMe4+] interactions with the aromatic motifs of naturally occurring amino acids: a theoretical study

Ab initio (HF, MP2, and CCSD(T)) and DFT (B3LYP) calculations were done in modeling the cation (H(+), Li(+), Na(+), K(+), Ca(2+), Mg(2+), NH(4)(+), and NMe(4)(+)) interaction with aromatic side chain motifs of four amino acids (viz., phenylalanine, tyrosine, tryptophan and histidine). As the metal ion approaches the pi-framework of the model systems, they form strongly bound cation-pi complexes, where the metal ion is symmetrically disposed with respect to all ring atoms. In contrast, proton prefers to bind covalently to one of the ring carbons. The NH(4)(+) and NMe(4)(+) ions have shown N-H...pi interaction and C-H...pi interaction with the aromatic motifs. The interaction energies of N-H...pi and C-H...pi complexes are higher than hydrogen bonding interactions; thus, the orientation of aromatic side chains in protein is effected in the presence of ammonium ions. However, the regioselectivity of metal ion complexation is controlled by the affinity of the site of attack. In the imidazole unit of histidine the ring nitrogen has much higher metal ion (as well as proton) affinity as compared to the pi-face, facilitating the in-plane complexation of the metal ions. The interaction energies increase in the order of 1-M < 2-M < 3-M < 4-M < 5-M for all the metal ion considered. Similarly, the complexation energies with the model systems decrease in the following order: Mg(2+) > Ca(2+) > Li(+) > Na(+) > K(+) congruent with NH(4)(+) > NMe(4)(+). The variation of the bond lengths and the extent of charge transfer upon complexation correlate well with the computed interaction energies.     

Synthesis and conformational analysis of new troponyl aromatic amino acid

Synthetic peptides are in huge demand in expansion of potential peptide mimics, which may have improved or comparable function as natural one. With these concerns, phenyl bearing aromatic amino acids and peptides has extensively explored, because phenyl residue has high probability in forming stable secondary structure, owing to the presence of an extra stabilizing factor as π–π non-covalent interactions. Apart from phenyl bearing benzenoid aromatic amino acids, a few non-benzenoid aromatic derivatives such as tropolone and related compounds are also occurred in nature, but troponyl containing amino acids and peptides are very poorly understood. Tropolonyl derivatives also contain carbonyl functional group, which may play an important role to provide stable conformation in peptide. Herein we report the synthesis, and conformational analysis of rationally designed new unnatural δ-amino acid, troponyl aminoethylglycine (Tr-aeg), which contains troponyl residue as side chain in flexible aminoethylglycine (aeg) amino acid backbone. We also demonstrate the role of troponyl carbonyl of Tr-aeg residue in hydrogen bonding with adjacent amide NH of their hybrid di/tri-peptides with NMR methods and DFT calculations. In future, Tr-aeg amino acid would be a potential building block in development of promisable peptide mimics.     

The influence of macrocyclic polyether constitution upon ammonium ion/crown ether recognition processes

Secondary dialkylammonium (R2NH2+) ions are bound readily by dibenzo[24]crown-8 (DB24C8) to form threaded complexes, namely [2]pseudo-rotaxanes. The effect of replacing one or both of the catechol rings in DB24C8 with resorcinol rings upon the crown ether's ability to bind R2NH2+ ions has now been investigated. When only one aromatic ring is changed from catechol to resorcinol, a crown ether with a [25]crown-8 constitution is created-namely benzometaphenylene[25]crown-8 (BMP25C8). A [2]pseudorotaxane is formed in the solid state when BMP25C8 is co-crystallized with dibenzylammonium hexafluorophosphate, as evidenced by its X-ray crystal structure. Furthermore, this crown ether has been shown to bind R2NH2+ ions in solution, an observation which has been exploited in the synthesis of the first BMP25C8-containing [2]rotaxane. The methodology employed to generate this [2]rotaxane--the reaction of an amine with an isocyanate to form a urea--was tested initially on a system incorporating DB24C8 and was shown to work efficiently. Both [2]rotaxanes have been fully characterized by 1H and 13C NMR spectroscopies, FAB mass spectrometry and X-ray crystallography. Interestingly, the unsymmetrical nature of the dumbbell-shaped component in each of the two [2]rotaxanes renders each face of the encircling macrocyclic polyether diastereotopic, a feature that is apparent upon inspection of their 1H NMR spectra. The resonances associated with the diastereotopic protons on each face of the macrorings are well enough resolved to enable the faces of the crown ethers to be readily identified with respect to their protons by 1H NMR spectroscopy. Unambiguous assignments can be made as a result of the fact that the protons on each face of the macrocyclic polyether experience a unique set of through-space interactions, as evidenced by T-ROESY experiments. Additionally, the two-dimensional NMR analyses are in agreement with the X-ray crystallographic studies performed on these [2]rotaxanes, indicating that the crown ethers are located intimately around the NH2+ centers as expected. Replacement of both catechol rings in the DB24C8 constitution with resorcinol rings results in a crown ether with a [26]crown-8 constitution--namely bismetaphenylene[26]crown-8 (BMP26CS). All the evidence to date points to the fact that this further change in constitution results in a crown ether that does not bind R2NH2+ ions in either the solution or solid states.     

Molecular self-assembly inhibition leads to basket-shaped cyclophane formation with chiral dynamics

Planar perylene derivatives form macrocyclic dimers and concatenated dimer-dimer rings under the action of molecular self-assembly. If this underpinning principle is true, highly twisted perylene derivatives should be more frustrated toward formation of multimeric cyclic compounds such as macrocyclic dimers and concatenated dimer-dimers because of perturbation resulting from intermolecular pi-pi stacking. Indeed, 1,6,7,12- tetraphenoxy-substituted perylene is highly twisted and undergoes unimolecular cyclization rather than bimolecular or multimolecular cyclization. The resulting monocyclic monomer exhibits interesting conformation switching from one chiral structure (left-handedness) to another chiral structure (right-handedness) at room temperature. NMR studies of conformational dynamics reveal that such configuration change between the two enantiomers can be frozen at low temperature (-45 degrees C). An activation enthalpy barrier of 13.4 +/- 0.5 kcal.mol-1 for twisting the perylene plane in order to convert from one enantiomer to the other has been found.     

The gas-phase dipeptide analogue acetyl-phenylalanyl-amide: a model for the study of side chain/backbone interactions in proteins

The issue of the influence of the side chain/backbone interaction on the local conformational preferences of a phenylalanine residue in a peptide chain is addressed. A synergetic approach is used, which combines gas-phase UV spectroscopy as well as gas-phase IR/UV double-resonance experiments with DFT and post Hartree-Fock calculations. N-Acetyl-Phe-amide was chosen as a model system for which three different conformers were observed. The most stable conformer has been identified as an extended beta(L) conformation of the peptide backbone. It is stabilized by a weak but significant NH-pi interaction bridging the aromatic ring on the residue (i) with the NH group on residue (i+1), with the aromatic side chain being in an anti conformation. This stable conformation corresponds to the common NH(i+1)-aromatic(i) interaction encountered in proteins for the three aromatic residues (phenylalanine, tyrosine, and tryptophan), which illustrates the relevance of gas-phase investigations to structural biology issues. The two other less abundant conformers have been assigned to two gamma-folded backbone conformations that differ by the orientation of the side chain. In all cases, the IR data provided spectroscopic fingerprints of these interactions. Finally, the strong conformational dependence of the fluorescence yield found for N-acetyl-Phe-amide illustrates the role of the environment on the excited-state dynamics of these species, which is often exploited by biochemists to monitor protein structural changes from tryptophan lifetime measurements.     

Is [N+-H...O] hydrogen bonding the most important noncovalent interaction in macrocycle-dibenzylammonium ion complexes?

We report a new host molecule in which one diethylene glycol chain (i.e., a loop possessing only three oxygen atoms) incorporated along with two phenolic aromatic rings is linked by a xylene spacer into a macroring. The design of the molecular structure of this macrocycle "amplifies" any potential [cation...pi], [N+-H...pi], and [N+C-H...pi] interactions between the dibenzylammonium (DBA+) ion and the phenolic rings of the macrocycle; as such, these species display a very strong binding affinity in CD3NO2 (Ka = 15,000 M(-1)). The macroring also coordinates to bipyridinium ions in a [2]pseudorotaxane fashion, which makes it the smallest macrocycle (i.e., a 25-membered ring) known to complex both DBA+ and bipyridinium ions in solution. To confirm unambiguously that these pseudorotaxanes exist in solution, we synthesized their corresponding interlocked molecules, namely rotaxanes and catenanes.