Metal‐Helix Frameworks from Short Hybrid Peptide Foldamers

The potential of structured peptides has not been explored much in the design of metal‐organic frameworks (MOFs). This is partly due to the difficulties in obtaining stable secondary structures from the short α‐peptide sequences. Here we report the design, crystal conformations, coordination site dependent different silver coordinated frameworks of short α,γ‐hybrid peptide 12‐helices consisting of terminal pyridyl moieties and the utility of metal‐helix frameworks in the adsorption of CO₂. Upon silver ion coordination the 12‐helix terminated by the 3‐pyridyl derivatives adopted a 2:2 macrocyclic structure, while the 12‐helix terminated by the 4‐pyridyl derivatives displayed remarkable porous metal‐helix frameworks. Both head‐to‐tail intermolecular H‐bonds of the 12‐helix and metal ion coordination have played an important role in stabilizing the ordered metal‐helix frameworks. The studies described here open the door to design a new class of metal‐organic‐frameworks from peptide foldamers.     

Metal–Helix Frameworks Formed by μ3-NO3− with Different Orientations and Connected to a Heterometallic CuII10DyIII2 Folded Cluster

Metal nanoclusters have a certain rigidity due to their specific coordination patterns and shapes; thus, they face extreme difficulty in folding into a specific direction to form a double-helix structure and in further interconnecting to form metal–helix frameworks (MHFs). To date, no MHFs have been produced by the formation of heterometallic clusters. Selecting the appropriate “bonding molecules” to bond metal nanoclusters in a specific multiple direction is one of the most effective strategies for designing synthetic MHFs. In this study, we realized for the first time the control of different orientations of μ₃-NO₃⁻ to join heterometallic clusters (Cu₁₀Dy₂) and subsequently form a left-handed double helix chain, which further joins to form MHFs. In the structure of the MHFs, four different directions of bridging μ₃-NO₃⁻ exist, three of which are involved in the linkage of the double-helix chain. Each μ₃-NO₃⁻ is connected to three adjacent Cu₁₀Dy₂. Herein, we extend a new method for designing synthetic double-helix structures and MHFs, thereby further laying the foundation for the development of similar DNA double-helix structures and nucleic acid secondary structures in vitro.     

Coordination‐Driven Folding and Assembly of a Short Peptide into a Protein‐like Two‐Nanometer‐Sized Channel

Short peptide helices have attracted attention as suitable building blocks for soft functional materials, but they are rarely seen in crystalline materials. A new artificial nanoassembly of short peptide helices in the crystalline state is presented in which peptide helices are arranged three‐dimensionally by metal coordination. The folding and assembly processes of a short peptide ligand containing the Gly‐Pro‐Pro sequence were induced by silver(I) coordination in aqueous alcohol, and gave rise to a single crystal composed of polyproline II helices. Crystallographic studies revealed that this material possesses two types of unique helical nanochannel; the larger channel measures more than 2 nm in diameter. Guest uptake properties were investigated by soaking the crystals in polar solutions of guest molecules; anions, organic chiral molecules, and bio‐oligomers are effectively encapsulated by this peptide‐folded porous crystal, with moderate to high chiral recognition for chiral molecules.     

手性多孔材料在色谱分离分析中的应用

手性多孔有机骨架材料(Chiral porous organic frameworks,CPOFs)具有孔性质优异、比表面积高、稳定性好以及易功能化等诸多优点,已经在手性催化、识别和分离等领域中得到应用。手性多孔有机骨架材料主要有手性金属-有机骨架材料(Chiral metal-organic frameworks,CMOFs)和手性共价有机骨架材料(Chiral covalent organic frameworks,CCOFs)及其他材料,这类材料具有特殊的手性识别、吸附作用,在色谱分离分析领域中已成为研究热点之一。该文综述了手性多孔材料的合成及其在色谱分离和选择性吸附中的应用,展望了未来CPOFs材料可能的应用与发展方向。     

Conformational Adaptation of β-Peptide Foldamers for the Formation of Metal–Peptide Frameworks

Metal-coordinated frameworks derived from small peptidic ligands have received much attention thanks to peptides’ vast structural and functional diversity. Various peptides with partial conformational preferences have been used to build metal–peptide frameworks, however, the use of conformationally constrained β-peptide foldamers has not been explored yet. Herein we report the first metal-coordination-mediated assembly of β-peptide foldamers with 12-helical folding propensity. The coordination of Ag⁺ to the terminal pyridyl moieties afforded a set of metal–peptide frameworks with unique entangled topologies. Interestingly, formation of the network structures was accompanied by notable conformational distortions of the foldamer ligands. As the first demonstration of new metal–peptide frameworks built from modular β-peptide foldamers, we anticipate that this work will be an important benchmark for further structural evolution and mechanistic investigation.     

Recent advances of application of porous molecular cages for enantioselective recognition and separation

Porous materials with well‐defined pore structures have received considerable attention in the past decades due to their unique structures and wide applications. Most porous materials such as zeolites, metal‐organic frameworks, covalent organic frameworks, and porous organic polymers are extended to infinite frameworks or networks by robust covalent or coordination bonds. Porous molecular cages composed of discrete molecules with permanent cavities are an emerging class of porous material and the discrete molecules assemble into solids by weak intermolecular interaction. In comparison to porous extended solids such as metal‐organic frameworks and covalent organic frameworks, porous molecular cage solids are generally soluble in organic solvents thus allowing solution processing, making them more convenient to apply in many fields. This review mainly focuses on the recent advances of application of porous molecular cages (porous organic cages and metal‐organic cages) for enantioselective recognition and separation from 2010 to present, including gas chromatography, capillary electrochromatography, chiral fluorescent recognition, chiral potentiometric sensing, and enantioselective adsorption. Furthermore, the two important family members of porous molecular cages, porous organic cages and metal‐organic cages, are also discussed.     

Hierarchical assembly of homochiral porous solids using coordination and hydrogen bonds

A family of homochiral metal carboxylate coordination polymers have been synthesized by treating 2,2'-dihydroxy-1,1'-binaphthalene-6,6'-dicarboxylic acid (H(2)BDA) with metal salts at elevated temperatures. BDA ligands link adjacent metal centers to form 1D coordination polymeric chains using the carboxylate functionality, while the hydroxyl groups of BDA ligands form H-bonds with carboxylate oxygen atoms to link 1D coordination polymeric chains into open frameworks of higher dimensionality. We also present evidence for the important role played by H-bonds in the stabilization of open framework structures which allows for the hierarchical assembly of chiral porous solids.     

Homochiral metal–organic framework used as a stationary phase for high‐performance liquid chromatography

Metal–organic frameworks are promising porous materials. Chiral metal–organic frameworks have attracted considerable attention in controlling enantioselectivity. In this study, a homochiral metal–organic framework [Co₂(D‐cam)₂(TMDPy)] (D‐cam = d ‐camphorates, TMDPy = 4,4′‐trimethylenedipyridine) with a non‐interpenetrating primitive cubic net has been used as a chiral stationary phase in high‐performance liquid chromatography. It has allowed the successful separation of six positional isomers and six chiral compounds. The good selectivity and baseline separation, or at least 60% valley separation, confirmed its excellent molecular recognition characteristics. The relative standard deviations for the retention time of run‐to‐run and column‐to‐column were less than 1.8 and 3.1%, respectively. These results demonstrate that [Co₂(D‐cam)₂(TMDPy)] may represent a promising chiral stationary phase for use in high‐performance liquid chromatography.     

Understanding metalloprotein folding using a de novo design strategy

Metal ions play significant roles in most biological systems. Over the past two decades, there has been significant interest in the redesign of existing metal binding sites in proteins/peptides and the introduction of metals into folded proteins/peptides. Recent research has focused on the effects of metal binding on the overall secondary and tertiary conformations of unstructured peptides/proteins. In this context, de novo design of metallopeptides has become a valuable approach for studying the consequence of metal binding. It has been seen that metal ions not only direct folding of partially folded peptides but have at times also been the elixir for properly folding random-coil-like structures in stable secondary conformations. Work in our group has focused on binding of heavy metal ions such as Hg(II) to de novo designed alpha-helical three stranded coiled coil peptides with sequences based on the heptad repeat motif. Removal from or addition of a heptad to the parent 30-residue TRI peptide with the amino acid sequence Ac-G(LKALEEK)(4)G-NH(2) generated peptides whose self-aggregation affinities were seen to be dependent on their lengths. It was noted that adjustment in the position of the thiol from an "a" position in the case of the shorter BabyL9C to a "d" position for BabyL12C resulted in a peptide with low association affinities for itself, weaker binding with Hg(II), and a considerably faster kinetic profile for metal insertion. Similar differences in thermodynamic and kinetic parameters were also noted for the longer TRI peptides. At the same time, metal insertion into the prefolded and longer TRI and Grand peptides has clearly demonstrated that the metal binding is both thermodynamically as well kinetically different from that to unassociated peptides.     

X-ray Crystallographic Observation of Chiral Transformations within a Metal–Peptide Pore

Porous metal complexes enable single-crystal X-ray crystallographic observation of included guests or reaction intermediates through simple soaking with the guests/substrates. Previous studies on this technique have often encountered difficulties in the observation of chiral structures because the host frameworks had no chirality. We synthesized a new metal–peptide porous complex through a folding-and-assembly strategy and utilized the chiral pore for trapping chiral guests. Chiral alcohols and ketones were successfully included within the pore. Crystallographic analyses clearly revealed not only their chemical structures but also chiral transformation events within the pore such as fixed conformations or an unstable hemiacetal formation.     

Vibrational Spectroscopy and Conformational Structure of Protonated Polyalanine Peptides Isolated in the Gas Phase

The conformational structures of protonated polyalanine peptides, Ala(n)H(+), have been investigated in the gas phase for n = 3, 4, 5, and 7 using a combination of resonant-infrared multiphoton dissociation (R-IRMPD) spectroscopy in the NH and OH stretch regions and quantum chemical calculations. Agreement between theoretical IR and experimental R-IRMPD spectral features has enabled the assignment of specific hydrogen-bonded conformational motifs in the short protonated peptides and revealed their conformational evolution under elevated-temperature conditions, as a function of increasing chain length. The shortest peptide, Ala(3)H(+), adopts a mixture of extended and cyclic chain conformations, protonated, respectively, at a backbone carbonyl or the N-terminus. The longer peptides adopt folded, cyclic, and globular charge-solvated conformations protonated at the N-terminus, consistent with previous ion-mobility studies. The longest peptide, Ala(7)H(+), adopts a globular conformation with the N-terminus completely charge-solvated, demonstrating the emergence of "physiologically relevant" intramolecular interactions in the peptide backbone. The computed conformational relative free energies highlight the importance of entropic contributions in these peptides.     

Protonation and coordination ability of small peptides – theoretical and experimental approaches for elucidation

This review deals with modern theoretical and experimental approaches as well as structural elucidation of small peptides (SP), their protonated forms and metal complexes. Free peptide bond rotation in amino acids (AA) and peptides yielded various conformers, which may possess differing biological activities. Inter- and/or intramolecular stacking observed in aromatic SP is another phenomenon typical for both peptide salts and complexes. These phenomenological effects can be successfully studied, both theoretically and experimentally, using a combination of the theoretical approximations and physical methods, such as electronic absorption spectroscopy, vibrational spectroscopy (including IR and Raman), nuclear magnetic resonance, mass spectrometry, as well as single-crystal X-ray diffraction. The physical and chemical properties of these systems can be precisely calculated by ab initio and DFT methods, varying basis sets and the results obtained allow elucidation of their conformations as a function of the reaction conditions (pH, type of the solvent, temperature, metal to ligand molar ratio). Although the 3-D structures of many peptides have been determined over the past decades, peptide crystallization is still a major obstacle to crystallographic work and the presence of chiral center/s adds further difficulties. For this reason, a specific part of the review is focused on the study of the absolute structure of the peptides, their salts and metal complexes, discussing the conformational preferences of the peptides during these processes. The available crystallographic data for metal complexes are successfully used for the correlation between the structures and the spectroscopic properties.     

Spontaneous resolution of chiral polyoxometalate-based compounds consisting of 3D chiral inorganic skeletons assembled from different helical units

Four enantiomerically pure 3D chiral POM-based compounds, [Ni(2)(bbi)(2)(H(2)O)(4)V(4)O(12)]2 H(2)O (1 a and 1 b) and [Co(bbi)(H(2)O)V(2)O(6)] (2 a and 2 b) (bbi=1,1'-(1,4-butanediyl)bisimidazole) based on the achiral ligand, different vanadate chains, and different metal centers have been synthesized by hydrothermal methods. Single-crystal X-ray diffraction analyses revealed that 1 a and 1 b, and 2 a and 2 b, respectively, are enantiomers. In 1 a and 1 b two kinds of vanadate chains with different screw axes link Ni cations to generate 3D chiral inorganic skeletons, which are connected by the achiral bbi ligands to form complicated 3D 3,4-connected chiral self-penetrating frameworks with (7(2)8)(7(2)8(2)9(2))(7(3)8(2)10) topology. They represent the first examples of chiral self-penetrating frameworks known for polyoxometalate (POM) systems. Contrary to 1 a and 1 b, in 2 a and 2 b the vanadate chains link Co(II) cations to generate 3D chiral inorganic skeletons, which are assembled from two kinds of heterometallic helical units of opposite chirality along the c axes. The chiral inorganic skeletons are connected by bbi to form 3D 3,4-connected chiral POM-based frameworks with (6(2)8)(2)(6(2)8(2)10(2)) topology. It is believed that the asymmetrical coordination modes of the metal cations in 1 a-2 b generate the initial chiral centers, and that the formation of the various helical units and the hydrogen bond interactions are responsible for preservation of the chirality and spontaneous resolution when the chirality is extended into the homochiral 3D-networks. This is the first known report of chiral POM-based compounds consisting of 3D chiral inorganic skeletons being obtained by spontaneous resolution upon crystallization in the absence of any chiral source, which may provide a rational strategy for synthesis of chiral POM-based compounds by using achiral ligands and POM helical units.     

Hybrid peptide design. Hydrogen bonded conformations in peptides containing the stereochemically constrained gamma-amino acid residue, gabapentin

The crystal structure of 12 peptides containing the conformationally constrained 1-(aminomethyl)cyclohexaneacetic acid, gabapentin (Gpn), are reported. In all the 39 Gpn residues conformationally characterized so far, the torsion angles about the Calpha-Cbeta and Cbeta-Cgamma bonds are restricted to the gauche conformation (+/-60 degrees ). The Gpn residue is constrained to adopt folded conformations resulting in the formation of intramolecularly hydrogen-bonded structures even in short peptides. The peptides Boc-Ac6c-Gpn-OMe 1 and Boc-Gpn-Aib-Gpn-Aib-OMe 2 provide examples of C7 conformation; peptides Boc-Gpn-Aib-OH 3, Boc-Ac6c-Gpn-OH 4, Boc-Val-Pro-Gpn-OH 5, Piv-Pro-Gpn-Val-OMe 6, and Boc-Gpn-Gpn-Leu-OMe 7 provide examples of C9 conformation; peptide Boc-Ala-Aib-Gpn-Aib-Ala-OMe 8 provides an example of C12 conformation and peptides Boc-betaLeu-Gpn-Val-OMe 9 and Boc-betaPhe-Gpn-Phe-OMe 10 provide examples of C13 conformation. Gpn peptides provide examples of backbone expanded mimetics for canonical alpha-peptide turns like the gamma (C7) and the beta (C10) turns. The hybrid betagamma sequences provide an example of a mimetic of the C13 alpha-turn formed by three contiguous alpha-amino acid residues. Two examples of folded tripeptide structures, Boc-Gpn-betaPhe-Leu-OMe 11 and Boc-Aib-Gpn-betaPhg-NHMe 12, lacking internal hydrogen bonds are also presented. An analysis of available Gpn residue conformations provides the basis for future design of folded hybrid peptides.     

Metallacyclopeptides: artificial analogues of naturally occurring peptides

Naturally occurring metalloproteins contain metal ions either to introduce a special reactivity or to stabilize a peptide structure. Since the early 1990s, chemists have been trying to use metal coordination for the fixation of short artificial peptides in well-defined cyclic structures. In this tutorial review a survey of the general approaches towards metallacyclopeptides as small cyclic peptide derivatives or as a part of a bigger alpha-helix (or beta-sheet) structure is given. In three case studies it is shown how naturally occurring compounds can be mimicked by metal coordination to non-natural peptide derivatives.     

Beta-Ala containing peptides: potentials in design and construction of bioactive peptides and protein secondary structure mimics

In recent years, there has been increasing interest in de novo design and construction of novel synthetic peptides that mimic protein secondary structures, i.e., turns, helices and sheets. The unique structural influences exerted by unsubstituted, non-coded, non-chiral beta-amino acid, i.e., beta-alanine (beta-Ala; 3- or beta- aminopropionic acid) on peptide backbone, when inserted into peptide chain comprised alpha-amino acids, offer an excellent opportunity to design and construct diverse well-defined three-dimensional structures. Our current understanding of folding-unfolding behavior of the beta-Ala residues relies primarily from an examination of conformational preferences of a large number of short cyclic- as well as acyclic beta-Ala containing peptides investigated using single crystal X-ray diffraction analysis. In addition, theoretical conformational energy calculations and different spectroscopic techniques: 1H NMR, FT-IR and CD, have also been employed although, to a lesser extent. The obtainable results tend to reveal overwhelming preferences of the beta-Ala moiety for the folded gauche (mu approximately +/-65+/-10 degrees conformation in cyclic- and for an extended trans (mu approximately +/-165+/-10 degrees) as well as gauche (mu approximately +/-65+/-10 degrees) orientations in acyclic beta-Ala containing peptides. The results also indicate that in short linear beta-Ala containing peptides, the specific influence of selective neighboring side-chain substituents e.g. linear- or cyclic symmetrically C(alpha,alpha)-disubstituted glycines and other conformational constraints, may be significant in controlling the overall folded-unfolded topographical features across the two methylene units (-CbetaH2-CalphaH2-) of the beta-Ala residue. Taking into consideration the wide occurrence of beta-Ala moiety in animal and plant kingdoms and the remarkable structural versatility of the peptides incorporating beta-Ala residue(s), together with appreciable resistance towards enzymatic degradation, hold strong promise for biophysicists and biochemists not only to design molecules that fold to mimic protein secondary structures but also to develop potent peptide analogs and peptidomimetics displaying unique pharmaceutical properties.     

Of folding and function: understanding active-site context through metalloenzyme design

In the emerging field of biomolecular design, the introduction of metal-binding sites into loop or turn regions of known protein scaffolds has been utilized to create unique metalloprotein and metallopeptide systems for study. This Forum Article highlights examples of the modular-turn-substitution approach to design and the range of structural and mechanistic questions to which this tool can be applied. Examples from the authors' laboratory are given to show that lanthanide-binding metallopeptides, and now a full metallohomeodomain, can be generated by modular substitution of a Ca-binding EF-hand loop into the unrelated scaffold, the engrailed helix-turn-helix motif. We have previously shown that these peptides bind trivalent Ln(III) ions and promote DNA and phosphate hydrolysis, the targeted function. Here, a series of chimeric peptides are presented that differ only in the ninth loop position [given in parentheses; Peptides P3N (Asn), P3E (Glu), P3A (Ala), and P3W(D) (Asp]. This residue, a putative second-shell ligand stabilizing a coordinated water, was found to influence not only metal affinity but also peptide folding. The affinity for Tb(III) was determined by Trp-Tb fluorescence resonance energy transfer and followed the order Ka = P3W(D) > P3A approximately P3E > P3N. However, circular dichroism (CD) titrations with EuCl3 showed that only P3W(D) and P3N folded to any extent upon metal binding, indicating that the Asp/Asn side chains stabilize the central loop structure and thus propagate folding of the peripheral helices, whereas neither Ala nor Glu appears to be interacting with the metal to organize the loop. Finally, we investigated the longer range context of a given loop substitution by cloning and expressing a lanthanide-binding homeodomain (C2), whose loop insertion sequence is analogous to that of peptide P3W(D). We find by CD that apo-C2 has a significant helical structure (approximately 25% alphahelicity), which increases further upon the addition of Tb(III) (approximately 32% alpha helicity). The protein's Tb(III) affinity is similar to that of the chimeric peptides. However, unlike previously reported metallopeptides, we find that EuC2 does not appreciably promote phosphate or DNA cleavage, which suggests a difference in metal accessibility in the context of the full domain. We have demonstrated that substituting beta turns with metal-binding turns does not necessarily require homologous parental scaffolds or small flexible peptides but rather relies on the structural similarity of the motifs flanking the turn.     

Advances in chiral separations of small peptides by capillary electrophoresis and chromatography

Many chemical and biological processes are controlled by the stereochemistry of small polypeptides (di‐, tri‐, tetra‐, penta‐, hexapeptides, etc). The biological importance of peptide stereoisomers is of great value. Therefore, the chiral resolution of peptides is an important issue in biological and medicinal sciences and drug industries. The chiral resolutions of peptide racemates have been discussed with the use of capillary electrophoresis and chromatographic techniques. The various chiral selectors used were polysaccharides, cyclodextrins, Pirkle types, macrocyclic antibiotics, crown ethers, imprinted polymers, etc. The stereochemistry of dipeptides is also discussed. Besides, efforts are made to explain the chiral recognition mechanisms, which will be helpful in understanding existing and developing new stereoselective analyses. Future perspectives of enantiomeric resolution are also predicted. Finally, the review concludes with the demand of enantiomeric resolution of all naturally occurring and synthetic peptides.     

Designer nanomaterials using chiral self-assembling peptide systems and their emerging benefit for society

Chirality is absolutely central in chemistry and biology. The recent findings of chiral self-assembling peptides' remarkable chemical complementarity and structural compatibility make it one of the most inspired designer materials and structures in nanobiotechnology. The emerging field of designer chemistry and biology further explores biological and medical applications of these simple D,L- amino acids through producing marvellous nanostructures under physiological conditions. These self-assembled structures include well-ordered nanofibers, nanotubes and nanovesicles. These structures have been used for 3-dimensional tissue cultures of primary cells and stem cells, sustained release of small molecules, growth factors and monoclonal antibodies, accelerated wound-healing in reparative and regenerative medicine as well as tissue engineering. Recent advances in molecular designs have also led to the development of 3D fine-tuned bioactive tissue culture scaffolds. They are also used to stabilize membrane proteins including difficult G-protein coupled receptors for designing nanobiodevices. One of the self-assembling peptides has been used in human clinical trials for accelerated wound-healings. It is our hope that these peptide materials will open doors for more and diverse clinical uses. The field of chiral self-assembling peptide nanobiotechnology is growing in a number of directions that has led to many surprises in areas of novel materials, synthetic biology, clinical medicine and beyond.     

Constraining Cyclic Peptides To Mimic Protein Structure Motifs

Many proteins exert their biological activities through small exposed surface regions called epitopes that are folded peptides of well‐defined three‐dimensional structures. Short synthetic peptide sequences corresponding to these bioactive protein surfaces do not form thermodynamically stable protein‐like structures in water. However, short peptides can be induced to fold into protein‐like bioactive conformations (strands, helices, turns) by cyclization, in conjunction with the use of other molecular constraints, that helps to fine‐tune three‐dimensional structure. Such constrained cyclic peptides can have protein‐like biological activities and potencies, enabling their uses as biological probes and leads to therapeutics, diagnostics and vaccines. This Review highlights examples of cyclic peptides that mimic three‐dimensional structures of strand, turn or helical segments of peptides and proteins, and identifies some additional restraints incorporated into natural product cyclic peptides and synthetic macrocyclic peptidomimetics that refine peptide structure and confer biological properties.