Aromatic Cages Research Articles

Exploring Aromatic Cage Flexibility Using Cosolvent Molecular Dynamics Simulations─An In-Silico Case Study of Tudor Domains.

Cosolvent molecular dynamics (MD) simulations have proven to be powerful in silico tools to predict hotspots for binding regions on protein surfaces. In the current study, the method was adapted and applied to two Tudor domain-containing proteins, namely Spindlin1 (SPIN1) and survival motor neuron protein (SMN). Tudor domains are characterized by so-called aromatic cages that recognize methylated lysine residues of protein targets. In the study, the conformational transitions from closed to open aromatic cage conformations were investigated by performing MD simulations with cosolvents using six different probe molecules. It is shown that a trajectory clustering approach in combination with volume and atomic distance tracking allows a reasonable discrimination between open and closed aromatic cage conformations and the docking of inhibitors yields very good reproducibility with crystal structures. Cosolvent MDs are suitable to capture the flexibility of aromatic cages and thus represent a promising tool for the optimization of inhibitors.

Piezofluorochromism in Hierarchical Porous π‐stacked Supermolecular Spring Frameworks from Aromatic Chiral Cages

AbstractPiezochromic materials that exhibit pressure‐dependent luminescence variations are attracting interest with wide potential applications in mechanical sensors, anticounterfeiting and storage devices. Crystalline porous materials (CPMs) have been widely studied in piezochromism for highly tunable luminescence. Nevertheless, reversible and high‐contrast emission response with a wide pressure range is still challenging. Herein, the first example of hierarchical porous cage‐based πOF (Cage‐πOF‐1) with spring structure was synthesized by using aromatic chiral cages as building blocks. Its elastic properties evaluated based on the bulk modulus (9.5 GPa) is softer than most reported CPMs and the collapse point (20.0 GPa) significantly exceeds ever reported CPMs. As smart materials, Cage‐πOF‐1 displays linear pressure‐dependent emission and achieves a high‐contrast emission difference up to 154 nm. Pressure‐responsive limit is up to 16 GPa, outperforming the CPMs reported so far. Dedicated experiments and density functional theory (DFT) calculations illustrate that π–π interactions‐dominated controllable structural shrinkage and porous‐spring‐structure‐mediated elasticity is responsible for the outstanding piezofluorochromism.

Piezofluorochromism in Hierarchical Porous π-stacked Supermolecular Spring Frameworks from Aromatic Chiral Cages.

Piezochromic materials that exhibit pressure-dependent luminescence variations are attracting interest with wide potential applications in mechanical sensors, anticounterfeiting and storage devices. Crystalline porous materials (CPMs) have been widely studied in piezochromism for highly tunable luminescence. Nevertheless, reversible and high-contrast emission response with a wide pressure range is still challenging. Herein, the first example of hierarchical porous cage-based πOF (Cage-πOF-1) with spring structure was synthesized by using aromatic chiral cages as building blocks. Its elastic properties evaluated based on the bulk modulus (9.5 GPa) is softer than most reported CPMs and the collapse point (20.0 GPa) significantly exceeds ever reported CPMs. As smart materials, Cage-πOF-1 displays linear pressure-dependent emission and achieves a high-contrast emission difference up to 154 nm. Pressure-responsive limit is up to 16 GPa, outperforming the CPMs reported so far. Dedicated experiments and density functional theory (DFT) calculations illustrate that π-π interactions-dominated controllable structural shrinkage and porous-spring-structure-mediated elasticity is responsible for the outstanding piezofluorochromism.

A porous aromatic cage-based electrochemical sensor for enantioselective recognition of DOPA.

An electrochemical sensor based on porous aromatic cages was reported, which can achieve chiral sensing of DOPA enantiomers. The prepared sensor can achieve a recognition efficiency of up to 2.6 for DOPA enantiomers. The enhanced recognition efficiency could be attributed to the cooperation of intermolecular interactions, and the efficient charge transfer process.

Selective Encapsulation and Chiral Induction of C60 and C70 Fullerenes by Axially Chiral Porous Aromatic Cages

AbstractChiral induction has been an important topic in chemistry, not only for its relevance in understanding the mysterious phenomenon of spontaneous symmetry breaking in nature but also due to its critical implications in medicine and the chiral industry. The induced chirality of fullerenes by host–guest interactions has been rarely reported, mainly attributed to their chiral resistance from high symmetry and challenges in their accessibility. Herein, we report two new pairs of chiral porous aromatic cages (PAC), R‐PAC‐2, S‐PAC‐2 (with Br substituents) and R‐PAC‐3, S‐PAC‐3 (with CH3 substituents) enantiomers. PAC‐2, rather than PAC‐3, achieves fullerene encapsulation and selective binding of C70 over C60 in fullerene carbon soot. More significantly, the occurrence of chiral induction between R‐PAC‐2, S‐PAC‐2 and fullerenes is confirmed by single‐crystal X‐ray diffraction and the intense CD signal within the absorption region of fullerenes. DFT calculations reveal the contribution of electrostatic effects originating from face‐to‐face arene‐fullerene interactions dominate C70 selectivity and elucidate the substituent effect on fullerene encapsulation. The disturbance from the differential interactions between fullerene and surrounding chiral cages on the intrinsic highly symmetric electronic structure of fullerene could be the primary reason accounting for the induced chirality of fullerene.

Selective Encapsulation and Chiral Induction of C60 and C70 Fullerenes by Axially Chiral Porous Aromatic Cages.

Chiral induction has been an important topic in chemistry, not only for its relevance in understanding the mysterious phenomenon of spontaneous symmetry breaking in nature but also due to its critical implications in medicine and the chiral industry. The induced chirality of fullerenes by host-guest interactions has been rarely reported, mainly attributed to their chiral resistance from high symmetry and challenges in their accessibility. Herein, we report two new pairs of chiral porous aromatic cages (PAC), R-PAC-2, S-PAC-2 (with Br substituents) and R-PAC-3, S-PAC-3 (with CH3 substituents) enantiomers. PAC-2, rather than PAC-3, achieves fullerene encapsulation and selective binding of C70 over C60 in fullerene carbon soot. More significantly, the occurrence of chiral induction between R-PAC-2, S-PAC-2 and fullerenes is confirmed by single-crystal X-ray diffraction and the intense CD signal within the absorption region of fullerenes. DFT calculations reveal the contribution of electrostatic effects originating from face-to-face arene-fullerene interactions dominate C70 selectivity and elucidate the substituent effect on fullerene encapsulation. The disturbance from the differential interactions between fullerene and surrounding chiral cages on the intrinsic highly symmetric electronic structure of fullerene could be the primary reason accounting for the induced chirality of fullerene.

Chiral self-sorting and guest recognition of porous aromatic cages

The synthesis of ultra-stable chiral porous organic cages (POCs) and their controllable chiral self-sorting at the molecular and supramolecular level remains challening. Herein, we report the design and synthesis of a serial of axially chiral porous aromatic cages (PAC 1-S and 1-R) with high chemical stability. The theoretical and experimental studies on the chiral self-sorting reveal that the exclusive self-recognition on cage formation is an enthalpy-driven process while the chiral narcissistic and self-sorting on supramolecular assembly of racemic cages can be precisely regulated by π–π and C–H…π interactions from different solvents. Regarding the chemical stability, the crystallinity of PAC 1 is maintained in aqueous solvents, such as boiling water, high-concentrated acid and alkali; mixtures of solvents, such as 1 M H2SO4/MeOH/H2O solution, are also tolerated. Investigations on the chiral sensing performance show that PAC 1 enables enantioselective recognition of axially chiral biaryl molecules.

Recognition of Dimethylarginine Analogues by Tandem Tudor Domain Protein Spindlin1.

Epigenetic readout of the combinatorial posttranslational modification comprised of trimethyllysine and asymmetric dimethylarginine (H3K4me3R8me2a) takes place via biomolecular recognition of tandem Tudor-domain-containing protein Spindlin1. Through comparative thermodynamic data and molecular dynamics simulations, we sought to explore the binding scope of asymmetric dimethylarginine mimics by Spindlin1. Herein, we provide evidence that the biomolecular recognition of H3K4me2R8me2a is not significantly affected when R8me2a is replaced by dimethylarginine analogues, implying that the binding of K4me3 provides the major binding contribution. High-energy water molecules inside both aromatic cages of the ligand binding sites contribute to the reader–histone association upon displacement by histone peptide, with the K4me3 hydration site being lower in free energy due to a flip of Trp151.

AroCageDB: A Web-Based Resource for Aromatic Cage Binding Sites and Their Intrinsic Ligands.

While aromatic cages have extensively been investigated in the context of structural biology, molecular recognition, and drug discovery, there exist to date no comprehensive resource for proteins sharing this conserved structural motif. To this end, we parsed the Protein Data Bank and thus constructed the Aromatic Cage Database (AroCageDB), a database for investigating the binding pocket descriptors and ligand binding space of aromatic-cage-containing proteins (ACCPs). AroCageDB contains 487 unique ACCPs bound to 890 unique ligands, for a total of 1636 complexes. This web-accessible database provides a user-friendly interface for the interactive visualization of ligand-bound ACCP structures, with a variety of search options that will open up opportunities for structural analyses and drug discovery campaigns. AroCageDB is freely available at http://www.pharmbioinf.uni-freiburg.de/arocagedb/.

Searching for methyllysine-binding aromatic cages

Methylation of lysine residues plays crucial roles in a wide variety of cell signaling processes. While the biological importance of recognition of methylated histones by reader domains in the cell nucleus is well established, the processes associated with methylation of non-histone proteins, particularly in the cytoplasm of the cell, are not well understood. Here, we describe a search for potential methyllysine readers using a rapid structural motif-mining algorithm Erebus, the PDB database, and knowledge of the methyllysine binding mechanisms.

Mechanism of biomolecular recognition of trimethyllysine by the fluorinated aromatic cage of KDM5A PHD3 finger

The understanding of biomolecular recognition of posttranslationally modified histone proteins is centrally important to the histone code hypothesis. Despite extensive binding and structural studies on the readout of histones, the molecular language by which posttranslational modifications on histone proteins are read remains poorly understood. Here we report physical-organic chemistry studies on the recognition of the positively charged trimethyllysine by the electron-rich aromatic cage containing PHD3 finger of KDM5A. The aromatic character of two tryptophan residues that solely constitute the aromatic cage of KDM5A was fine-tuned by the incorporation of fluorine substituents. Our thermodynamic analyses reveal that the wild-type and fluorinated KDM5A PHD3 fingers associate equally well with trimethyllysine. This work demonstrates that the biomolecular recognition of trimethyllysine by fluorinated aromatic cages is associated with weaker cation–π interactions that are compensated by the energetically more favourable trimethyllysine-mediated release of high-energy water molecules that occupy the aromatic cage.

A Two Carrier Families Spectral Profile Model for Anomalous Microwave Emission

Abstract We model anomalous microwave emission (AME) spectral profiles from 14 diverse galactic and extragalactic sources. The spectral profile model is an analytic representation of a quantum mechanical model for symmetric top rotational emission. The observed spectral shapes are well fit by superposing two model profiles originating from two distinct carrier families. Each family is composed of numerous, comparably abundant isomers of a parent carrier. The isomers have similar rotational constants, thereby producing continuous, versus resolved line, spectra that are slightly broader than the parent profiles. Ten observations are fit with comparable peak height and peak frequency ratios for the two carrier families, suggesting that AME arises from common carriers. One observation is fit using a single family, attributed to photodissociation of the less stable, smaller molecules for the missing family. Three observations are fit by combining two frequency-shifted model spectra, indicating multiple sources along their sight lines. The derived rotational constants for the two parent carriers are well determined because their rotational temperature is well characterized for the LDN 1622 dark cloud AME source. The rotational constants are consistent with the C36 and C60 fullerenes as the parent carriers. We use a Monte Carlo simulation of fullerene hydrogenation to understand the origins of source variability in the AME model fits. Other potential carriers, polycyclic aromatic hydrocarbons and very small grains, cannot be excluded; however, we find that fulleranes are also viable carriers because their aromatic cages are extremely stable to photodissociation, and their data-derived sizes suggest C36 and C60 parent fullerenes.

Tuning the Solubility of Self-Assembled Fluorescent Aromatic Cages Using Functionalized Amino Acid Building Blocks.

We previously reported novel fluorescent aromatic cages that are self-produced using a set of orthogonal dynamic covalent reactions, operating simultaneously in one-pot, to assemble up to 10 components through 12 reactions into a single cage-type structure. We now introduce N-functionalized amino acids as new building blocks that enable tuning the solubility and analysis of the resulting cages. A convenient divergent synthetic approach was developed to tether different side chains on the N-terminal of a cysteine-derived building block. Our studies show that this chemical functionalization does not prevent the subsequent self-assembly and effective formation of desired cages. While the originally described cages required 94% DMSO, the new ones bearing hydrophobic side chains were found soluble in organic solvents (up to 75% CHCl3), and those grafted with hydrophilic side chains were soluble in water (up to 75% H2O). Fluorescence studies confirmed that despite cage functionalization the aggregation-induced emission properties of those architectures are retained. Thus, this work significantly expands the range of solvents in which these self-assembled cage compounds can be generated, which in turn should enable new applications, possibly as fluorescent sensors.

Deciphering chemical bonding in BnHn2−(n = 2–17): flexible multicenter bonding

Deciphering flexible multicenter bonding incloso-borane dianions BnHn2−.

Structure-Activity Relationships of Cbx7 Inhibitors, Including Selectivity Studies against Other Cbx Proteins.

The five human polycomb (Pc) paralog proteins, chromobox homolog (Cbx) 2/4/6/7/8, are a family of chromodomain containing methyllysine reader proteins that are canonical readers of trimethyllysine 27 on histone 3 (H3K27me3). The aberrant expression of the Cbx7 gene is implicated in several cancers including prostate, gastric, thyroid, pancreas, and colon cancer. Previous reports on antagonizing the molecular recognition of Cbx7–H3K27me3 with chemical inhibitors showed an impact on prostate cancer cell lines. We report here on the design, synthesis, and structure–activity relationships of a series of potent peptidomimetic antagonists that were optimized on a trimethyllysine-containing scaffold to target Cbx7. The ligands were characterized using fluorescence polarization (FP) for their binding efficiency and selectivity against the Pc paralog Cbx proteins. The most selective ligand 9, as indicated by the FP data analysis, was further characterized using the isothermal titration calorimetry (ITC). Compound 9 exhibits a 220 nM potency for Cbx7 and exhibits 3.3, 1.8, 7.3 times selective for Cbx7 over Cbx2/4/8 and 28-fold selective over the HP1 family member Cbx1. Our research provides several potent and partially selective inhibitors for Cbx2/4/7 that do not contain trimethyllysine. Our models and binding data suggest that the aromatic cages of Cbx7/Cbx4 can accommodate larger alkyl groups such as diisobutyl substitution on the lysine nitrogen.

A computational insight into the interaction of methylated lysines with aromatic amino acid cages

Posttranslational lysine methylations in histone proteins are recognized by specific reader proteins. The interaction proceeds through the binding of methylated lysine to the aromatic cages created by the combinations of tryptophan and/or tyrosine and/or phenylalanine, and it is specific to the degree of methylation of lysine residue. The chemical recognition is based on cation-π interaction between positively charged lysine and the π system of the aromatic groups. In this study, the energetics of the binding of model methylated Lys to the model aromatic amino acids as well as aromatic cages are investigated with density functional theory calculations. Molecular orbitals corresponding to the bound complexes and separate lysine and aromatic amino acid components are analyzed. Finally, using single-point energy calculations, the feasibility of comparing binding energies/affinities of methylated lysines with different methylation degrees is shown, using available crystal structures of the bound model complexes.

Aromatic cages B: unprecedented existence of octagonal holes in boron clusters.

The cage-like structures containing octagonal holes are located as the lowest-lying isomers for the B. The presence of octagonal holes, which have been found for the first time, not only gives us new insight into the bonding motif, but also marks a breakthrough in the structural characteristics of boron clusters since they were never expected to be stable units for elemental clusters. These cages are composed of both delocalized σ and π electron systems that consequently make them aromatic and thermodynamically stable.

Correction: Aromatic cages B₄₂⁰/⁺: unprecedented existence of octagonal holes in boron clusters.

Correction for 'Aromatic cages B42(0/+): unprecedented existence of octagonal holes in boron clusters' by Truong Ba Tai et al., Phys. Chem. Chem. Phys., 2016, DOI: 10.1039/c5cp07342a.

Selective molecular recognition of methylated lysines and arginines by cucurbit[6]uril and cucurbit[7]uril in aqueous solution

Cucurbit[7]uril selectively binds the epigenetic mark N(ε),N(ε),N(ε)-trimethyllysine (LysMe(3), K(CB[7]) = (1.8 ± 0.6)× 10(6) dm(3) mol(-1)) by 3500-fold over lysine ((5.3 ± 0.7) × 10(2) dm(3) mol(-1)) in aqueous solution, using ion-dipole interactions and the hydrophobic effect, rather than cation-π interactions, as in the "aromatic cages" of p-SO(3)-calix[4]arene hosts or chromodomain proteins which recognize LysMe(3). The trend in K(CB[7]) of LysMe(3) > LysMe(2) > LysMe > Lys follows the recognition pattern of the chromodomain HP1 and other LysMe(n) protein readers. With CB[6], protonation of the guest carboxylate group is required for the formation of inclusion complexes with the LysMe(n) series. The CB[7] host also displays modest selectivity between the asymmetric ((2.0 ± 0.3) × 10(3) dm(3) mol(-1)) and symmetric ((6.1 ± 0.6) × 10(3) dm(3) mol(-1)) dimethylarginines, both of which bind more strongly than the parent arginine or monomethylarginine.

Modular incorporation of 1-benzyltryptophan into dipeptide hosts that bind acetylcholine in pure water

Proteins that recognize and bind quaternary ammonium ions depend on “aromatic-cage” structural motifs that use multiple aromatic residues to engage the side chain’s ammonium cation. We introduce herein the use of 1-benzyltryptophan (Trp(Bn)) residues as synthetic, unnatural partial analogues of natural aromatic cages. We demonstrate the modular incorporation of these building blocks into simple dipeptide hosts and show that they are capable of binding quaternary ammonium ions in buffered water and in chloroform.