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Molecular Recognition and Self-Assembly in Chemistry and Medicine

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A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Chemical Biology".

Deadline for manuscript submissions: closed (15 October 2020) | Viewed by 37805

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Prof. Dr. Valeria Amendola

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Department of Chemistry, Università di Pavia, Viale Taramelli, 12‐27100 Pavia, Italy
Interests: supramolecular chemistry; molecular recognition; chemosensing; molecular cages and containers; self-assembly; molecular machines

Special Issue Information

Dear Colleagues,

Molecular recognition and self-assembly are key processes, often strictly related to each other, involved in many chemical and biological systems. In the supramolecular context, the self-assembly of molecular components to yield a supra-molecular product generally involves a series of steps, driven by synergistic non-covalent interactions between the building blocks. Notably, the final multicomponent assembly often displays novel functions, even recognition capabilities, that were non-existent in the starting materials. Depending on the counterparts (e.g., neutral molecules and/or charged species), the driving force in molecular recognition and self-assembly processes may include different types of interactions such as hydrogen and halogen bonding, π−π stacking, metal-to-ligand, charge-transfer interactions, and electrostatic forces. The last twenty years have seen the spread of this supramolecular approach in various fields, from material science to medicine. Self-assembly and self-sorting, for instance, underlie the creation of metal–organic materials, such as polyhedral cages and polymeric networks, which are now applied, e.g., as sensors or supercapacitors, as materials in separation and purification processes, as nano-reactors, or as catalysts. In addition, the self-assembly of organic molecules such as amphiphiles, either assisted or not by metal ions, is widely employed in the development of novel soft materials (e.g., supramolecular gels, micelles, and polymers) with interesting responsive behaviors and potential applications in technology and medicine.

The present Special Issue aims to provide an update on molecular recognition and self-assembly, with a special focus on recent applications in chemistry and medicine.

Prof. Dr. Valeria Amendola
Guest Editor

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Keywords

molecular recognition
chemosensing devices
self-assembled systems
molecular cages
nano-reactors
non-covalent interactions

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Published Papers (11 papers)

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25 pages, 49090 KiB

Open AccessArticle

Glyconectin Cell Adhesion Epitope, β-d-GlcpNAc3S-(1→3)-α-l-Fucp, Is Involved in Blastulation of Lytechinus pictus Sea Urchin Embryos

by Gradimir Misevic, Iacob Checiu and Octavian Popescu

Molecules 2021, 26(13), 4012; https://doi.org/10.3390/molecules26134012 - 30 Jun 2021

Viewed by 2468

Abstract

Glycans, as the most peripheral cell surface components, are the primary candidates to mediate the initial steps of cell recognition and adhesion via glycan–glycan binding. This molecular mechanism was quantitatively demonstrated by biochemical and biophysical measurements at the cellular and molecular level for the glyconectin 1 β-d-GlcpNAc3S-(1→3)-α-l-Fucp glycan structure (GN1). The use of adhesion blocking monoclonal antibody Block 2 that specifically recognize this epitope showed that, besides Porifera, human colon carcinoma also express this structure in the apical glycocalyx. Here we report that Block 2 selectively immune-precipitate a Mr 580 × 10³ (g580) acidic non-glycosaminoglycan glycan from the total protein-free glycans of Lytechinus pictus sea urchin hatched blastula embryos. Immuno-fluorescence confocal light microscopy and immunogold electron microscopy localized the GN1 structure in the apical lamina glycocalyx attachments of ectodermal cells microvilli, and in the Golgi complex. Biochemical and immune-chemical analyses showed that the g580 glycan is carrying about 200 copies of the GN1 epitope. This highly polyvalent g580 glycan is one of the major components of the glycocalyx structure, maximally expressed at hatched blastula and gastrula. The involvement of g580 GN1 epitope in hatched blastula cell adhesion was demonstrated by: (1) enhancement of cell aggregation by g580 and sponge g200 glycans, (2) inhibition of cell reaggregation by Block 2, (3) dissociation of microvilli from the apical lamina matrix by the loss of its gel-like structure resulting in a change of the blastula embryonal form and consequent inhibition of gastrulation at saturating concentration of Block 2, and (4) aggregation of beads coated with the immune-purified g580 protein-free glycan. These results, together with the previous atomic force microscopy measurements of GN1 binding strength, indicated that this highly polyvalent and calcium ion dependent glycan–glycan binding can provide the force of 40 nanonewtons per single ectodermal cell association of microvilli with the apical lamina, and conservation of glycocalyx gel-like structure. This force can hold the weight of 160,000 cells in sea water, thus it is sufficient to establish, maintain and preserve blastula form after hatching, and prior to the complete formation of further stabilizing basal lamina. Full article

(This article belongs to the Special Issue Molecular Recognition and Self-Assembly in Chemistry and Medicine)

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18 pages, 1524 KiB

Open AccessArticle

Aromatic Rings as Molecular Determinants for the Molecular Recognition of Protein Kinase Inhibitors

by Yan Zhu, Saad Alqahtani and Xiche Hu

Molecules 2021, 26(6), 1776; https://doi.org/10.3390/molecules26061776 - 22 Mar 2021

Cited by 15 | Viewed by 3583

Abstract

Protein kinases are key enzymes in many signal transduction pathways, and play a crucial role in cellular proliferation, differentiation, and various cell regulatory processes. However, aberrant function of kinases has been associated with cancers and many other diseases. Consequently, competitive inhibition of the ATP binding site of protein kinases has emerged as an effective means of curing these diseases. Over the past three decades, thousands of protein kinase inhibitors (PKIs) with varying molecular frames have been developed. Large-scale data mining of the Protein Data Bank resulted in a database of 2139 non-redundant high-resolution X-ray crystal structures of PKIs bound to protein kinases. This provided us with a unique opportunity to study molecular determinants for the molecular recognition of PKIs. A chemoinformatic analysis of 2139 PKIs resulted in findings that PKIs are “flat” molecules with high aromatic ring counts and low fractions of sp³ carbon. All but one PKI possessed one or more aromatic rings. More importantly, it was found that the average weighted hydrogen bond count is inversely proportional to the number of aromatic rings. Based on this linear relationship, we put forward the exchange rule of hydrogen bonding interactions and non-bonded π-interactions. Specifically, a loss of binding affinity caused by a decrease in hydrogen bonding interactions is compensated by a gain in binding affinity acquired by an increase in aromatic ring-originated non-bonded interactions (i.e., π–π stacking interactions, CH–π interactions, cation–π interactions, etc.), and vice versa. The very existence of this inverse relationship strongly suggests that both hydrogen bonding and aromatic ring-originated non-bonded interactions are responsible for the molecular recognition of PKIs. As an illustration, two representative PKI–kinase complexes were employed to examine the relative importance of different modes of non-bonded interactions for the molecular recognition of PKIs. For this purpose, two FDA-approved PKI drugs, ibrutinib and lenvatinib, were chosen. The binding pockets of both PKIs were thoroughly examined to identify all non-bonded intermolecular interactions. Subsequently, the strengths of interaction energies between ibrutinib and its interacting residues in tyrosine kinase BTK were quantified by means of the double hybrid DFT method B2PLYP. The resulting energetics for the binding of ibrutinib in tyrosine kinase BTK showed that CH–π interactions and π–π stacking interactions between aromatic rings of the drug and hydrophobic residues in its binding pocket dominate the binding interactions. Thus, this work establishes that, in addition to hydrogen bonding, aromatic rings function as important molecular determinants for the molecular recognition of PKIs. In conclusion, our findings support the following pharmacophore model for ATP-competitive kinase inhibitors: a small molecule features a scaffold of one or more aromatic rings which is linked with one or more hydrophilic functional groups. The former has the structural role of acting as a scaffold and the functional role of participating in aromatic ring-originated non-bonded interactions with multiple hydrophobic regions in the ATP binding pocket of kinases. The latter ensure water solubility and form hydrogen bonds with the hinge region and other hydrophilic residues of the ATP binding pocket. Full article

(This article belongs to the Special Issue Molecular Recognition and Self-Assembly in Chemistry and Medicine)

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16 pages, 4963 KiB

Open AccessArticle

Achiral Molecular Recognition of Substituted Aniline Position Isomers by Crown Ether Type Chiral Stationary Phase

by Atsushi Ohnishi, Tohru Shibata, Tatsuya Imase, Satoshi Shinkura and Kanji Nagai

Molecules 2021, 26(2), 493; https://doi.org/10.3390/molecules26020493 - 18 Jan 2021

Cited by 11 | Viewed by 2867

Abstract

To understand the selectivity of the crown ether type chiral stationary phase (CSP), the retention selectivity for aniline and the positional isomers of substituted anilines were studied. In various substituted isomers, except nitroaniline, a remarkable decrease of retention due to steric hindrance was observed for the 2-substituted isomer. To determine the detailed molecular recognition mechanism, quantum chemical calculations were performed for the aggregates between the crown ether and the anilines. The results suggested that the 20-Crown-6, which includes a phenyl-substituted 1,1′-binaphthyl moiety, interacts with alkyl and aryl amines in an unconventional form different from the proposed one for 18-Crown-6. Full article

(This article belongs to the Special Issue Molecular Recognition and Self-Assembly in Chemistry and Medicine)

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21 pages, 4844 KiB

Open AccessArticle

Functionalization of Polyethyleneimine with Hollow Cyclotriveratrylene and Its Subsequent Supramolecular Interaction with Doxorubicin

by Carmine Coluccini, Yoke Mooi Ng, Yves Ira A. Reyes, Hsin-Yi Tiffany Chen and Yit Lung Khung

Molecules 2020, 25(22), 5455; https://doi.org/10.3390/molecules25225455 - 20 Nov 2020

Cited by 9 | Viewed by 3343

Abstract

In this paper, a modified Cyclotriveratrylene was synthesized and linked to a branched Polyethylenimine, and this unique polymeric material was subsequently examined as a potential supramolecular carrier for Doxorubicin. Spectroscopic analysis in different solvents had shown that Doxorubicin was coordinated within the hollow-shaped unit of the armed Cyclotriveratrylene, and the nature of the host–guest complex revealed intrinsic Van der Waals interactions and hydrogen bonding between the host and guest. The strongest interaction was detected in water because of the hydrophobic effect shared between the aromatic groups of the Doxorubicin and Cyclotriveratrylene unit. Density functional theory calculations had also confirmed that in the most stable coordination of Doxorubicin with the cross-linked polymer, the aromatic rings of the Doxorubicin were localized toward the Cyclotriveratrylene core, while its aliphatic chains aligned closer with amino groups, thus forming a compact supramolecular assembly that may confer a shielding effect on Doxorubicin. These observations had emphasized the importance of supramolecular considerations when designing a novel drug delivery platform. Full article

(This article belongs to the Special Issue Molecular Recognition and Self-Assembly in Chemistry and Medicine)

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15 pages, 3549 KiB

Open AccessArticle

Binding Modes of a Phenylpyridinium Styryl Fluorescent Dye with Cucurbiturils

by Adrien Paudics, Dóra Hessz, Márton Bojtár, Benjámin Gyarmati, András Szilágyi, Mihály Kállay, István Bitter and Miklós Kubinyi

Molecules 2020, 25(21), 5111; https://doi.org/10.3390/molecules25215111 - 3 Nov 2020

Cited by 8 | Viewed by 3758

Abstract

In order to explore how cucurbituril hosts accommodate an N-phenyl-pyridinium derivative guest, the complexation of the solvatochromic dye, 4-(4-(dimethylamino)styryl)-1-phenylpyridinium iodide (PhSt) with α,α′,δ,δ′-tetramethyl-cucurbit[6]uril (Me₄CB6) and cucurbit[7]uril (CB7) was investigated by absorption spectroscopic, fluorescence and NMR experiments. In aqueous solutions, PhSt forms 1:1 complexes with both cucurbiturils, the complex with CB7 has a higher stability constant (K_a = 6.0 × 10⁶ M⁻¹) than the complex with Me₄CB6 (K_a = 1.1 × 10⁶ M⁻¹). As revealed by NMR experiments and confirmed by theoretical calculations, CB7 encapsulates the whole phenylpyridinium entity of the PhSt cation guest, whereas the cavity of Me₄CB6 includes only the phenyl ring, the pyridinium ring is bound to the carbonyl rim of the host. The binding of PhSt to cucurbiturils is accompanied by a strong enhancement of the fluorescence quantum yield due to the blocking of the deactivation through a twisted intramolecular charge transfer (TICT) state. The TICT mechanism in PhSt was characterized by fluorescence experiments in polyethylene glycol (PEG) solvents of different viscosities. The PhSt-CB7 system was tested as a fluorescence indicator displacement (FID) assay, and it recognized trimethyl-lysine selectively over other lysine derivatives. Full article

(This article belongs to the Special Issue Molecular Recognition and Self-Assembly in Chemistry and Medicine)

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12 pages, 2160 KiB

Open AccessCommunication

Towards Building Blocks for Supramolecular Architectures Based on Azacryptates

by Ana Miljkovic, Sonia La Cognata, Greta Bergamaschi, Mauro Freccero, Antonio Poggi and Valeria Amendola

Molecules 2020, 25(7), 1733; https://doi.org/10.3390/molecules25071733 - 9 Apr 2020

Cited by 6 | Viewed by 2812

Abstract

In this work, we report the synthesis of a new bis(tris(2-aminoethyl)amine) azacryptand L with triphenyl spacers. The binding properties of its dicopper complex for aromatic dicarboxylate anions (as TBA salts) were investigated, with the aim to obtain potential building blocks for supramolecular structures like rotaxanes and pseudo-rotaxanes. As expected, UV-Vis and emission studies of [Cu₂L]⁴⁺ in water/acetonitrile mixture (pH = 7) showed a high affinity for biphenyl-4,4′-dicarboxylate (dfc²⁻), with a binding constant of 5.46 log units, due to the best match of the anion bite with the Cu(II)-Cu(II) distance in the cage’s cavity. Compared to other similar bistren cages, the difference of the affinity of [Cu₂L]⁴⁺ for the tested anions was not so pronounced: conformational changes of L seem to promote a good interaction with both long (e.g., dfc²⁻) and short anions (e.g., terephthalate). The good affinity of [Cu₂L]⁴⁺ for these dicarboxylates, together with hydrophobic interactions within the cage’s cavity, may promote the self-assembly of a stable 1:1 complex in water mixture. These results represent a good starting point for the application of these molecular systems as building units for the design of new supramolecular architectures based on non-covalent interactions, which could be of interest in all fields related to supramolecular devices. Full article

(This article belongs to the Special Issue Molecular Recognition and Self-Assembly in Chemistry and Medicine)

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10 pages, 1133 KiB

Open AccessFeature PaperArticle

Binaphthyl-Based Macrocycles as Optical Sensors for Aromatic Diphenols

by Stefano Piacentini, Marco Caricato, Aurora Pacini, Andrea Nitti and Dario Pasini

Molecules 2020, 25(3), 514; https://doi.org/10.3390/molecules25030514 - 24 Jan 2020

Viewed by 2923

Abstract

The synthesis of several rigid, homochiral organic macrocycles possessing, respectively, average molecular D₂ and D₃ symmetries, is described. They have been obtained from aromatic dicarboxylic acids, in combination with an axially-chiral, suitable dibenzylic alcohol, derived from 1,1′-binaphthyl-2,2′-diol (BINOL) using one-pot esterification reactions in good isolated yields. NMR and circular dichroism (CD) spectroscopies detect the structural and shape variability in the scaffolds, reflected both in terms of the changes in chemical shifts and the shape of selected proton resonances, and in terms of the variation of the CD signature related to the dihedral angle defined by the binaphthyl units embedded in the rigid cyclic skeleton. The D₂ cyclic adducts are able to form stable complexes with aromatic diphenols, with binding strengths that are dependent on small variations in the spacing units, and therefore on the shapes of the internal cavities of the cyclic structures. Full article

(This article belongs to the Special Issue Molecular Recognition and Self-Assembly in Chemistry and Medicine)

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11 pages, 1166 KiB

Open AccessArticle

Hypotonic, Acidic Oxidizing Solution Containing Hypochlorous Acid (HClO) as a Potential Treatment of Hailey-Hailey Disease

by Samantha Cialfi, Salvatore Calabro, Matteo Franchitto, Azzurra Zonfrilli, Isabella Screpanti and Claudio Talora

Molecules 2019, 24(24), 4427; https://doi.org/10.3390/molecules24244427 - 4 Dec 2019

Cited by 6 | Viewed by 3385

Abstract

Hailey–Hailey disease (HHD) is a rare, chronic and recurrent blistering disorder, characterized by erosions occurring primarily in intertriginous regions and histologically by suprabasal acantholysis. Mutation of the Golgi Ca²⁺-ATPase ATP2C1 has been identified as having a causative role in Hailey–Hailey disease. HHD-derived keratinocytes have increased oxidative-stress that is associated with impaired proliferation and differentiation. Additionally, HHD is characterized by skin lesions that do not heal and by recurrent skin infections, indicating that HHD keratinocytes might not respond well to challenges such as wounding or infection. Hypochlorous acid has been demonstrated in vitro and in vivo to possess properties that rescue both oxidative stress and altered wound repair process. Thus, we investigated the potential effects of a stabilized form of hypochlorous acid (APR-TD012) in an in vitro model of HHD. We found that treatment of ATP2C1-defective keratinocytes with APR-TD012 contributed to upregulation of Nrf2 (nuclear factor (erythroid-derived 2)-like 2). Additionally, APR TD012-treatment restored the defective proliferative capability of siATP2C1-treated keratinocytes. We also found that the APR-TD012 treatment might support wound healing process, due to its ability to modulate the expression of wound healing associated cytokines. These observations suggested that the APR-TD012 might be a potential therapeutic agent for HHD-lesions. Full article

(This article belongs to the Special Issue Molecular Recognition and Self-Assembly in Chemistry and Medicine)

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12 pages, 1537 KiB

Open AccessArticle

Synthesis of a Novel Zn-Salphen Building Block and Its Acrylic Terpolymer Counterparts as Tunable Supramolecular Recognition Systems

by Gustavo A. Zelada-Guillén, Ana B. Cuéllar-Sánchez, Margarita Romero-Ávila and Martha V. Escárcega-Bobadilla

Molecules 2019, 24(12), 2245; https://doi.org/10.3390/molecules24122245 - 15 Jun 2019

Cited by 6 | Viewed by 3963

Abstract

In this work, we present the synthesis of a novel Zn-Salphen complex containing an allyl group, which was used as building block in the further preparation of a new family of functional terpolymers. These polymers were obtained through radical co-polymerization with methyl metacrylate (MMA) and n-butyl acrylate (nBuA) in different ratios. The supramolecular recognition behavior of each polymer was evaluated via potentiometric measurements against selected anions in aqueous media. Interestingly, this proof of concept study shows that these systems were selective against only fluoride (F⁻) or both, fluoride and acetate (OAc⁻), by tailoring the relative content of Zn-Salphen monomer, thus making them a promising starting point for modular design of chemical sensors through straightforward synthetic approaches. Full article

(This article belongs to the Special Issue Molecular Recognition and Self-Assembly in Chemistry and Medicine)

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31 pages, 5438 KiB

Open AccessReview

Glycan-to-Glycan Binding: Molecular Recognition through Polyvalent Interactions Mediates Specific Cell Adhesion

by Gradimir Misevic and Emanuela Garbarino

Molecules 2021, 26(2), 397; https://doi.org/10.3390/molecules26020397 - 13 Jan 2021

Cited by 10 | Viewed by 4154

Abstract

Glycan-to-glycan binding was shown by biochemical and biophysical measurements to mediate xenogeneic self-recognition and adhesion in sponges, stage-specific cell compaction in mice embryos, and in vitro tumor cell adhesion in mammals. This intermolecular recognition process is accepted as the new paradigm accompanying high-affinity and low valent protein-to-protein and protein-to-glycan binding in cellular interactions. Glycan structures in sponges have novel species-specific sequences. Their common features are the large size >100 kD, polyvalency >100 repeats of the specific self-binding oligosaccharide, the presence of fucose, and sulfated and/or pyruvylated hexoses. These structural and functional properties, different from glycosaminoglycans, inspired their classification under the glyconectin name. The molecular mechanism underlying homophilic glyconectin-to-glyconectin binding relies on highly polyvalent, strong, and structure-specific interactions of small oligosaccharide motifs, possessing ultra-weak self-binding strength and affinity. Glyconectin localization at the glycocalyx outermost cell surface layer suggests their role in the initial recognition and adhesion event during the complex and multistep process. In mammals, Le^x-to-Le^x homophilic binding is structure-specific and has ultra-weak affinity. Cell adhesion is achieved through highly polyvalent interactions, enabled by clustering of small low valent structure in plasma membranes. Full article

(This article belongs to the Special Issue Molecular Recognition and Self-Assembly in Chemistry and Medicine)

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29 pages, 11252 KiB

Open AccessReview

Molecular Recognition and Self-Organization in Life Phenomena Studied by a Statistical Mechanics of Molecular Liquids, the RISM/3D-RISM Theory

by Masatake Sugita, Itaru Onishi, Masayuki Irisa, Norio Yoshida and Fumio Hirata

Molecules 2021, 26(2), 271; https://doi.org/10.3390/molecules26020271 - 7 Jan 2021

Cited by 11 | Viewed by 3308

Abstract

There are two molecular processes that are essential for living bodies to maintain their life: the molecular recognition, and the self-organization or self-assembly. Binding of a substrate by an enzyme is an example of the molecular recognition, while the protein folding is a good example of the self-organization process. The two processes are further governed by the other two physicochemical processes: solvation and the structural fluctuation. In the present article, the studies concerning the two molecular processes carried out by Hirata and his coworkers, based on the statistical mechanics of molecular liquids or the RISM/3D-RISM theory, are reviewed. Full article

(This article belongs to the Special Issue Molecular Recognition and Self-Assembly in Chemistry and Medicine)

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