Aromatic Stacking Interactions Research Articles

Pristine and Hydroxylated Fullerenes Prevent the Aggregation of Human Islet Amyloid Polypeptide and Display Different Inhibitory Mechanisms.

Protein aggregation, involving the formation of dimers, oligomers, and fibrils, is associated with many human diseases. Type 2 diabetes is one of the common amyloidosis and linked with the aggregation of human islet amyloid polypeptide (hIAPP). A series of nanoparticles are reported to be able to interact with proteins and enhance/inhibit protein aggregation. However, the effects of C60 (a model system of hydrophobic nanoparticle) and C60(OH)8 (a hydroxylated fullerene) on hIAPP aggregation remain unknown. In this study, we investigate the influences of pristine fullerene C60 and hydroxylated C60 on the dimerization of hIAPP using molecular dynamics (MD) simulations. Extensive replica exchange molecular dynamics (REMD) simulations show that isolated hIAPP dimers adopt β-sheet structure containing the amyloid-precursor (β-hairpin). Both C60 and C60(OH)8 notably inhibit the β-sheet formation of hIAPP dimer and induce the formation of collapsed disordered coil-rich conformations. Protein—nanoparticle interaction analyses reveal that the inhibition of hIAPP aggregation by C60 is mainly via hydrophobic and aromatic-stacking interactions, while the prevention of hIAPP aggregation by C60(OH)8 is mostly through collective hydrogen bonding and aromatic-stacking interactions. Conventional MD simulations indicate that both C60 and C60(OH)8 weaken the interactions within hIAPP protofibril and disrupt the β-sheet structure. These results provide mechanistic insights into the possible inhibitory mechanism of C60 and C60(OH)8 toward hIAPP aggregation, and they are of great reference value for the screening of potent amyloid inhibitors.

Slow ring flips in aromatic cluster of GB1 studied by aromatic 13C relaxation dispersion methods

Ring flips of phenylalanine and tyrosine are a hallmark of protein dynamics. They report on transient breathing motions of proteins. In addition, flip rates also depend on stabilizing interactions in the ground state, like aromatic stacking or cation–π interaction. So far, experimental studies of ring flips have almost exclusively been performed on aromatic rings without stabilizing interactions. Here we investigate ring flip dynamics of Phe and Tyr in the aromatic cluster in GB1. We found that all four residues of the cluster, Y3, F30, Y45 and F52, display slow ring flips. Interestingly, F52, the central residue of the cluster, which makes aromatic contacts with all three others, is flipping significantly faster, while the other rings are flipping with the same rates within margin of error. Determined activation enthalpies and activation volumes of these processes are in the same range of other reported ring flips of single aromatic rings. There is no correlation of the number of aromatic stacking interactions to the activation enthalpy, and no correlation of the ring’s extent of burying to the activation volume. Because of these findings, we speculate that F52 is undergoing concerted ring flips with each of the other rings.

Construction of a series of Zn(II) and Cd(II) coordination polymers bearing 1,3-bis(benzimidazol-1-yl)-2-propanol ligands: Syntheses, crystal structures, and sensing properties

Five coordination polymers (CPs), namely {[Zn(L)(ip)·H2O]8}n (1), {[Zn(L)(2-ntp)]·H2O}n (2), {[Zn(L)(tdc)·2H2O]2}n (3), {[Cd(L)(tp)·H2O]·3.43H2O}n (4) and [Cd(L)(5-mip)]n (5) (L ​= ​1,3-bis(benzimidazol-1-yl)-2-propanol, H2ip ​= ​isophthalic acid, 2-H2ntp ​= ​2-nitroterephthalic acid, H2tdc ​= ​2,5-thiophenedicarboxylic acid, H2tp ​= ​terephthalic acid and 5-H2mip ​= ​5-methylisophthalic acid) have been hydrothermally synthesized. 1 exhibits a 3D 4-connected coordination framework with the rarely (86)-hxg/p topology. 2 is 2D (6,3) network incorporating [Zn2(L)2] loops, and further extended into a 3D supramolecular framework by O–H⋯O hydrogen bondings. 3 possesses a three-fold interpenetrated diamond network. 4 also forms a 2D (6, 3) layer, which is extended to a 3D supramolecular framework by the aromatic stacking interactions. 5 displays a 3,5-connected 3D 3,5T1 framework with a point symbol of {42·65·83}{42·6}. Further, 1 and 2 exhibit highly selectivity and sensitivity for luminescence sensing of acetone/Cr2O72− anions in aqueous solution, respectively.

Self-Assembly and Molecular Recognition in Water: Tubular Stacking and Guest-Templated Discrete Assembly of Water-Soluble, Shape-Persistent Macrocycles.

Supramolecular chemistry in aqueous media is an area with great fundamental and practical significance. To examine the role of multiple noncovalent interactions in controlled assembling and binding behavior in water, the self-association of five water-soluble hexakis(m-phenylene ethynylene) (m-PE) macrocycles, along with the molecular recognition behavior of the resultant assemblies, is investigated with UV-vis, fluorescence, CD, and NMR spectroscopy, mass spectrometry, and computational studies. In contrast to their different extents of self-aggregation in organic solvents, all five macrocycles remain aggregated in water at concentrations down to the micromolar (μM) range. CD spectroscopy reveals that 1-F6 and 1-H6, two macrocycles carrying chiral side chains and capable of H-bonded self-association, assemble into tubular stacks. The tubular stacks serve as supramolecular hosts in water, as exemplified by the interaction of macrocycles 1-H6 and 2-H6 and guests G1 through G4, each having a rod-like oligo(p-phenylene ethynylene) (p-PE) segment flanked by two hydrophilic chains. Fluorescence and 1H NMR spectroscopy revealed the formation of kinetically stable, discrete assemblies upon mixing 2-H6 and a guest. The binding stoichiometry, determined with fluorescence, 1H NMR, and ESI-MS, reveals that the discrete assemblies are novel pseudorotaxanes, each containing a pair of identical guest molecules encased by a tubular stack. The two guest molecules define the number of macrocyclic molecules that comprise the host, which curbs the "infinite" stack growth, resulting in a tubular stack with a cylindrical pore tailoring the length of the p-PE segment of the bound guests. Each complex is stabilized by the action of multiple noncovalent forces including aromatic stacking, side-chain H-bonding, and van der Waals interactions. Thus, the interplay of multiple noncovalent forces aligns the molecules of macrocycles 1 and 2 into tubular stacks with cylindrical inner pores that, upon binding rod-like guests, lead to tight, discrete, and well-ordered tubular assemblies that are unprecedented in water.

Expanding the structural diversity of peptide assemblies by coassembling dipeptides with diphenylalanine.

Molecular self-assembly is a bottom-up approach to fabricate novel supramolecular structures. While the structural diversity obtained by the use of a single type of building block is limited, coassembly of different peptides has recently evolved as an extended strategy to expand the diversity of peptide nanoarchitectures. Here we systematically investigate the coassembly of diphenylalanine (FF) with each one of the 399 non-FF dipeptides by micro-second molecular dynamics simulations. Our simulations show that dipeptides, by coassembling with FF, display a greatly enhanced aggregation propensity and a significantly expanded structural diversity. Regular-shaped vesicles, single- or multi-cavity assemblies, and planar sheets are formed by coassembly of FF with different types of non-FF dipeptides, which are rarely observed in self-assemblies of non-FF dipeptides. Interaction analyses reveal that the formation of these varied structures is attributed to a delicate balance between aromatic stacking, hydrophobic, and electrostatic repulsion interactions. This study provides structural and mechanistic insights into the coassembly of FF and non-FF dipeptides, thus offering a possible way to achieve a controllable design of bionanomaterials through FF-involved dipeptide coassembly.

Turning on solid-state phosphorescence of platinum acetylides with aromatic stacking.

Neat solids that phosphoresce under ambient conditions are rare due to aggregation-caused quenching. This communication describes a platinum acetylide (PtPE) that phosphoresces as a solid due to programmed aromatic stacking interactions of pendant groups that prevent intermolecular aggregation.

Recognition of Lewis X by Anti-Lex Monoclonal Antibody IG5F6.

mAbs directed toward the Lewis X (Lex) determinant have been shown to display different specificities, depending on the presentation of Lex to the immune system. Of interest is the murine anti-Lex mAb IG5F6, generated against the O chain polysaccharide of Helicobacter pylori that contains polymeric Lex structures. The mAb was found to have a higher affinity for polymeric Lex over monomeric Lex In this study, we explore the recognition of monomeric Lex by IG5F6 using a panel of Lex analogues in which N-acetyl-d-glucosamine, l-fucose, or d-galactose (D-Gal) are replaced with d-glucose and/or l-rhamnose. Our studies show that all analogues were weaker inhibitors than the Lex Ag, indicating that all three residues are essential in the recognition of Lex by mAb IG5F6. We explored the involvement of 4″-OH of d-Gal in the binding with IG5F6 using a panel of 4″-modified Lex analogues. Although the 4″-OH is only involved in a weak polar interaction, we conclude that the D-Gal residue in Lex is primarily involved in aromatic stacking interactions with the Ab binding site. We compared these results to our work with mAb SH1. Although stacking interactions between D-Gal and an aromatic residue was also suggested for SH1, an H-bond involving the 4″-OH was identified that is not found in the binding of IG5F6 to Lex Thus, anti-Lex mAbs SH1 and IG5F6 bind to Lex in different manners, even though the hydrophobic patch displayed by the β-galactoside in Lex is essential in both cases for their binding to Lex.

Directed Molecular Stacking for Engineered Fluorescent Three-Dimensional Reduced Graphene Oxide and Coronene Frameworks.

Three‐dimensional fluorescent graphene frameworks with controlled porous morphologies are of significant importance for practical applications reliant on controlled structural and electronic properties, such as organic electronics and photochemistry. Here we report a synthetically accessible approach concerning directed aromatic stacking interactions to give rise to new fluorogenic 3D frameworks with tuneable porosities achieved through molecular variations. The binding interactions between the graphene‐like domains present in the in situ‐formed reduced graphene oxide (rGO) with functional porphyrin molecules lead to new hybrids via an unprecedented solvothermal reaction. Functional free‐base porphyrins featuring perfluorinated aryl groups or hexyl chains at their meso‐ and β‐positions were employed in turn to act as directing entities for the assembly of new graphene‐based and foam‐like frameworks and of their corresponding coronene‐based hybrids. Investigations in the dispersed phase and in thin‐film by XPS, SEM and FLIM shed light onto the nature of the aromatic stacking within functional rGO frameworks (denoted rGOFs) which was then modelled semi‐empirically and by DFT calculations. The pore sizes of the new emerging reduced graphene oxide hybrids are tuneable at the molecular level and mediated by the bonding forces with the functional porphyrins acting as the “molecular glue”. Single crystal X‐ray crystallography described the stacking of a perfluorinated porphyrin with coronene, which can be employed as a molecular model for understanding the local aromatic stacking order and charge transfer interactions within these rGOFs for the first time. This opens up a new route to controllable 3D framework morphologies and pore size from the Ångstrom to the micrometre scale. Theoretical modelling showed that the porosity of these materials is mainly due to the controlled inter‐planar distance between the rGO, coronene or graphene sheets. The host‐guest chemistry involves the porphyrins acting as guests held through π‐π stacking, as demonstrated by XPS. The objective of this study is also to shed light into the fundamental localised electronic and energy transfer properties in these new molecularly engineered porous and fluorogenic architectures, aiming in turn to understand how functional porphyrins may exert stacking control over the notoriously disordered local structure present in porous reduced graphene oxide fragments. By tuning the porosity and the distance between the graphene sheets using aromatic stacking with porphyrins, it is also possible to tune the electronic structure of the final nanohybrid material, as indicated by FLIM experiments on thin films. Such nanohybrids with highly controlled pores dimensions and morphologies open the way to new design and assembly of storage devices and applications incorporating π‐conjugated molecules and materials and their π‐stacks may be relevant towards selective separation membranes, water purification and biosensing applications.

Using Small-Molecule Probes to Investigate Aggregation of Sunset Yellow FCF: What are the Concentration Limits?

The assembly of small molecules into larger structures, often driven by noncovalent interactions such as hydrogen bonding, aromatic stacking interactions, and burial of hydrophobic surface, is of widespread interest. The interaction of small molecules with aggregates also has a large range of applications from fluorescence aggregation assays to gas storage in framework materials. Here, we utilize nuclear magnetic resonance spectroscopy to investigate the interaction of a small-molecule probe on the assembly state of sunset yellow across a wide range of relative concentrations. Information from both macroscopic (diffusion) and microscopic (chemical shifts) measurements allows the interaction to be studied and the binding mode to be interrogated. Using fluorophenol as the small-molecule probe, we show that the aggregation behavior of sunset yellow is broadly unaffected by the relative amount of fluorophenol added.

Syntheses, crystal structures and photocatalytic properties of three zinc (II) coordination polymers constructed by mixed ligands

Three coordination polymers (CPs), namely, {[Zn(L1)(muoc)]·H2O}n (1), {[Zn(L2)(muoc)]2}n (2) and {[Zn(L2)(SA)]2}n (3), where L1 = L = 1,3-bis(benzimidazol-1-yl)-2-propanol, L2 = 1,3-bis(5,6-dimethylbenzimidazol-1-yl)-2-propanol, H2muoc = trans,trans-muconic acid and H2SA = succinic acid, have been hydrothermally synthesized and characterized by single crystal X-ray diffraction, elemental analysis, IR spectroscopy, powder X-ray diffraction (PXRD) and thermogravimetric analyses. 1 is 2D (6,3) network. 2 possesses a 2D (4,4) network, and the 2D layers are further packed into the 3D supramolecular framework by O–H⋯O hydrogen bonding interactions. 3 forms a 1D cyclic chain and further extend into 3D supramolecular framework by O–H⋯O hydrogen bonding and the aromatic stacking interactions. The photocatalytic properties of three CPs for degradation of methylene blue (MB) upon UV light irradiation were further investigated.

Structural diversity in polymeric and discrete complexes constructed by divalent transition metals and unsymmetrical quasi semirigid pyridinecarboxylate isomers

Nine polymeric and discrete complexes including a couple of genuine supramolecular isomers have been successfully prepared from divalent transition metal ions (Mn(II), Co(II), Ni(II), Cu(II), and Zn(II)) and unsymmetrical quasi semirigid pyridinecarboxylate isomers, InMe-n-py (n = 2, 3, 4). Structural analyses reveal that the unsymmetrical quasi semirigid ligands manage the metal(II) ions to form discrete (0D) armed metallocycle and dinuclear paddlewheel molecule, 1D ribbon, simple 2D rhombus (4,4) grid, 2D chiral wavy square (4,4) grid, and 2D double-edged layer with decorated (4,4) topology. Noncovalent hydrogen bonds and aromatic stacking interactions are found to be accessorial secondary interactions that are helpful for the extension and stabilization of the final inorganic−organic hybrid supramolecular networks of metal(II) complexes. Positional isomerism and conformational diversity of the unsymmetrical quasi semirigid ligands and the coordination preference of divalent metal ions play key roles in dominating structure variation and network complexity. Thermogravimetric analysis of mass loss showed that the frameworks of these complexes are thermally stable up to ca. 220–400 °C. Variable-temperature, solid-state magnetic susceptibility studies suggest that Mn(II) complexes 1 and 2 exhibit antiferromagnetic exchange coupling.

Tunable Supramolecular Gel Properties by Varying Thermal History.

The possibility of using differential pre-heating prior to supramolecular gelation to control the balance between hydrogen-bonding and aromatic stacking interactions in supramolecular gels and obtain consequent systematic regulation of structure and properties is demonstrated. Using a model aromatic peptide amphiphile, Fmoc-tyrosyl-leucine (Fmoc-YL) and a combination of fluorescence, infrared, circular dichroism and NMR spectroscopy, it is shown that the balance of these interactions can be adjusted by temporary exposure to elevated temperatures in the range 313-365 K, followed by supramolecular locking in the gel state by cooling to room temperature. Distinct regimes can be identified regarding the balance between H-bonding and aromatic stacking interactions, with a transition point at 333 K. Consequently, gels can be obtained with customizable properties, including supramolecular chirality and gel stiffness. The differential supramolecular structures also result in changes in proteolytic stability, highlighting the possibility of obtaining a range of supramolecular architectures from a single molecular structure by simply controlling the pre-assembly temperature.

Photo- and Aromatic Stacking-Induced Green Emissive Peptidyl Nanoparticles for Cell Imaging and Monitoring of Nucleic Acid Delivery.

Owing to their potential applications in biomedicine and biotechnology, peptide nanostructures that exhibit stable intrinsicfluorescence in the visible range are highly desired. This research proposes a facile strategy to construct peptidyl virus-like nanoparticles (NVPs) that show green luminescence by coassembly of two bioactive ferrocene-diphenylalanine-based (Fc-FF) peptides. The green fluorescence of NVPs was originated from the highly ordered structures assembled by the amphiphilic Fc-FF-based peptides via strong π-π stacking interactions. In the assemblies, Fc-FF chromophore can be hydrolyzed under the natural light irradiation, which eliminates the fluorophore quenching effect of Fc and increases the aromatic stacking interactions, thereby giving rise to strong fluorescent nanoparticles. The NVPs could cross cytomembrane barriers by virtue of the HIV V3 peptide and the nuclear localization signal, and could thus be used for long-term cell imaging with excellent photostability and biocompatibility in physiological condition. In addition, NVPs could package DNA and be used to monitor the delivery of DNA, indicating great potential in the tracking and monitoring of genetic biological processes.

Correction to "Additivity of Substituent Effects in Aromatic Stacking Interactions".

Correction to "Additivity of Substituent Effects in Aromatic Stacking Interactions".

The Norepinephrine Inhibits Alzheimer's Amyloid-β Peptide Aggregation by Binding to the C-Terminal Hydrophobic Region

The abnormal self-assembly of amyloid-β (Aβ) peptides into toxic prefibrillar aggregates is associated with the pathogenesis of Alzheimer's disease (AD). The inhibition of β-sheet-rich oligomers formation is considered as the primary therapeutic strategy for AD. Previous experimental studies reported that norepinephrine (NE), one of the neurotransmitters, is able to inhibit Aβ aggregation and disaggregate the preformed fibrils. However, the underlying inhibitory and disruptive mechanisms remain elusive. In this work, we performed extensive replica-exchange molecular dynamic (REMD) simulations on the conformational ensemble of Aβ1-42 dimer with and without NE molecules. Our results show that in the absence of NE molecules, Aβ1-42 dimer transiently adopts a β-hairpin involving two β-strands of residues 15QKLVFFA21 and residues 33GLMVGGVV40, whose β-strand regions strongly resemble those of the Aβ fibril structure (β1: residues Q15-A21, β2: residues I30-G37) reported in an electron paramagnetic resonance spectroscopy study. NE molecules greatly reduce the interpeptide β-sheet content and suppress the formation of the above-mentioned β-hairpin, leading to a more disordered coil-rich Aβ dimer. Four dominant binding sites are identified via contact probability and binding energy analyses, among which the C-terminal I31-V36 hydrophobic region is the most favorable one. Our data reveal that hydrophobic, aromatic stacking, cation-π and hydrogen-bonding interactions synergistically contribute to the NE-induced conformational shift. This work reveals the molecular mechanism of NE molecules against Aβ1-42 aggregation and provides valuable information for the development of new drug candidates against AD.

Norepinephrine Inhibits Alzheimer's Amyloid-β Peptide Aggregation and Destabilizes Amyloid-β Protofibrils: A Molecular Dynamics Simulation Study.

The abnormal self-assembly of amyloid-β (Aβ) peptides into toxic fibrillar aggregates is associated with the pathogenesis of Alzheimer's disease (AD). The inhibition of β-sheet-rich oligomer formation is considered as the primary therapeutic strategy for AD. Previous experimental studies reported that norepinephrine (NE), one of the neurotransmitters, is able to inhibit Aβ aggregation and disaggregate the preformed fibrils. Moreover, exercise can markedly increase the level of NE. However, the underlying inhibitory and disruptive mechanisms remain elusive. In this work, we performed extensive replica-exchange molecular dynamic (REMD) simulations to investigate the conformational ensemble of Aβ1-42 dimer with and without NE molecules. Our results show that without NE molecules, Aβ1-42 dimer transiently adopts a β-hairpin-containing structure, and the β-strand regions of this β-hairpin (residues 15QKLVFFA21 and 33GLMVGGVV40) strongly resemble those of the Aβ fibril structure (residues 15QKLVFFA21 and 30AIIGLMVG37) reported in an electron paramagnetic resonance spectroscopy study. NE molecules greatly reduce the interpeptide β-sheet content and suppress the formation of the above-mentioned β-hairpin, leading to a more disordered coil-rich Aβ dimer. Five dominant binding sites are identified, and the central hydrophobic core 16KLVFFA21 site and C-terminal 31IIGLMV36 hydrophobic site are the two most favorable ones. Our data reveal that hydrophobic, aromatic stacking, hydrogen-bonding and cation-π interactions synergistically contribute to the binding of NE molecules to Aβ peptides. MD simulations of Aβ1-42 protofibril show that NE molecules destabilize Aβ protofibril by forming H-bonds with residues D1, A2, D23, and A42. This work reveals the molecular mechanism by which NE molecules inhibit Aβ1-42 aggregation and disaggregate Aβ protofibrils, providing valuable information for developing new drug candidates and exercise therapy against AD.

Supramolecular cage encapsulation as a versatile tool for the experimental quantification of aromatic stacking interactions.

The widespread presence of aromatic stacking interactions in chemical and biological systems, combined with their relatively small energetic contribution, have led to a plethora of theoretical and experimental studies for their quantification and rationalization. Typically, π-π aromatic interactions are studied as a function of substituents to gather information about the interaction mechanism. While experiments suggest that aromatic interactions are dominated by local electrostatic contacts between π-electron density and CH groups, theoretical work has raised the possibility that direct electrostatic interactions between local dipoles of the substituents may play a role. We describe a supramolecular cage that binds two aromatic carboxylates in a stacked geometry such that the aromatic substituents are remote in space. Chemical Double Mutant Cycles (DMCs) were used to measure fifteen different aromatic stacking interactions as a function of substituent (NMe2, OMe, Me, Cl and NO2). When both aromatic rings have electron-withdrawing nitro substituents, the interaction is attractive (-2.8 kJ mol-1) due to reduced π-electron repulsion. When both aromatic rings have electron-donating di-methylamino substituents, the interaction is repulsive (+2.0 kJ mol-1) due to increased π-electron repulsion. The results show that aromatic stacking interactions are dominated by short range electrostatic contacts rather than substituent dipole interactions.

Programmed twisting of phenylene–ethynylene linkages from aromatic stacking interactions

Intramolecular aromatic stacking of ortho-pentafluorobenzyl benzoate esters enables the rational design of conformations of conjugated materials by programming twisted phenylene–ethynylene linkages reliably.

Study of through-space substituent–π interactions using N-phenylimide molecular balances

Substituent–π interactions associated with aromatic stacking interactions were experimentally measured using a small N-phenylimide molecular balance model system.

Mechano-responsive luminescent emissions of an organic molecular crystal: effects of aromatic stacking interactions and solid state packing

Three polymorphs of 2-hydroxynaphthaldehyde semicarbazone (2-NOH-S) have been identified, and their mechano-responsive luminescent emissions and interconversions are discussed.