Research

13 pages, 11062 KiB

Open AccessArticle

Hyaluronic Acid and a Short Peptide Improve the Performance of a PCL Electrospun Fibrous Scaffold Designed for Bone Tissue Engineering Applications

by Dana Rachmiel, Inbar Anconina, Safra Rudnick-Glick, Michal Halperin-Sternfeld, Lihi Adler-Abramovich and Amit Sitt

Int. J. Mol. Sci. 2021, 22(5), 2425; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22052425 - 12 Mar 2021

Cited by 20 | Viewed by 4462

Abstract

Bone tissue engineering is a rapidly developing, minimally invasive technique for regenerating lost bone with the aid of biomaterial scaffolds that mimic the structure and function of the extracellular matrix (ECM). Recently, scaffolds made of electrospun fibers have aroused interest due to their [...] Read more.

Bone tissue engineering is a rapidly developing, minimally invasive technique for regenerating lost bone with the aid of biomaterial scaffolds that mimic the structure and function of the extracellular matrix (ECM). Recently, scaffolds made of electrospun fibers have aroused interest due to their similarity to the ECM, and high porosity. Hyaluronic acid (HA) is an abundant component of the ECM and an attractive material for use in regenerative medicine; however, its processability by electrospinning is poor, and it must be used in combination with another polymer. Here, we used electrospinning to fabricate a composite scaffold with a core/shell morphology composed of polycaprolactone (PCL) polymer and HA and incorporating a short self-assembling peptide. The peptide includes the arginine-glycine-aspartic acid (RGD) motif and supports cellular attachment based on molecular recognition. Electron microscopy imaging demonstrated that the fibrous network of the scaffold resembles the ECM structure. In vitro biocompatibility assays revealed that MC3T3-E1 preosteoblasts adhered well to the scaffold and proliferated, with significant osteogenic differentiation and calcium mineralization. Our work emphasizes the potential of this multi-component approach by which electrospinning, molecular self-assembly, and molecular recognition motifs are combined, to generate a leading candidate to serve as a scaffold for bone tissue engineering. Full article

(This article belongs to the Special Issue Molecular Recognition in Biological and Bioengineered Systems)

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9 pages, 1951 KiB

Open AccessArticle

Substrate Scope for Human Histone Lysine Acetyltransferase KAT8

by Giordano Proietti, Yali Wang, Chiara Punzo and Jasmin Mecinović

Int. J. Mol. Sci. 2021, 22(2), 846; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22020846 - 15 Jan 2021

Cited by 10 | Viewed by 3091

Abstract

Biomedically important histone lysine acetyltransferase KAT8 catalyses the acetyl coenzyme A-dependent acetylation of lysine on histone and other proteins. Here, we explore the ability of human KAT8 to catalyse the acetylation of histone H4 peptides possessing lysine and its analogues at position 16 [...] Read more.

Biomedically important histone lysine acetyltransferase KAT8 catalyses the acetyl coenzyme A-dependent acetylation of lysine on histone and other proteins. Here, we explore the ability of human KAT8 to catalyse the acetylation of histone H4 peptides possessing lysine and its analogues at position 16 (H4K16). Our synthetic and enzymatic studies on chemically and structurally diverse lysine mimics demonstrate that KAT8 also has a capacity to acetylate selected lysine analogues that possess subtle changes on the side chain and main chain. Overall, this work highlights that KAT8 has a broader substrate scope beyond natural lysine, and contributes to the design of new chemical probes targeting KAT8 and other members of the histone lysine acetyltransferase (KAT) family. Full article

(This article belongs to the Special Issue Molecular Recognition in Biological and Bioengineered Systems)

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37 pages, 13245 KiB

Open AccessArticle

Identification of the Primary Factors Determining the Specificity of Human VKORC1 Recognition by Thioredoxin-Fold Proteins

by Maxim Stolyarchuk, Julie Ledoux, Elodie Maignant, Alain Trouvé and Luba Tchertanov

Int. J. Mol. Sci. 2021, 22(2), 802; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22020802 - 14 Jan 2021

Cited by 6 | Viewed by 2088

Abstract

Redox (reduction–oxidation) reactions control many important biological processes in all organisms, both prokaryotes and eukaryotes. This reaction is usually accomplished by canonical disulphide-based pathways involving a donor enzyme that reduces the oxidised cysteine residues of a target protein, resulting in the cleavage of [...] Read more.

Redox (reduction–oxidation) reactions control many important biological processes in all organisms, both prokaryotes and eukaryotes. This reaction is usually accomplished by canonical disulphide-based pathways involving a donor enzyme that reduces the oxidised cysteine residues of a target protein, resulting in the cleavage of its disulphide bonds. Focusing on human vitamin K epoxide reductase (hVKORC1) as a target and on four redoxins (protein disulphide isomerase (PDI), endoplasmic reticulum oxidoreductase (ERp18), thioredoxin-related transmembrane protein 1 (Tmx1) and thioredoxin-related transmembrane protein 4 (Tmx4)) as the most probable reducers of VKORC1, a comparative in-silico analysis that concentrates on the similarity and divergence of redoxins in their sequence, secondary and tertiary structure, dynamics, intraprotein interactions and composition of the surface exposed to the target is provided. Similarly, hVKORC1 is analysed in its native state, where two pairs of cysteine residues are covalently linked, forming two disulphide bridges, as a target for Trx-fold proteins. Such analysis is used to derive the putative recognition/binding sites on each isolated protein, and PDI is suggested as the most probable hVKORC1 partner. By probing the alternative orientation of PDI with respect to hVKORC1, the functionally related noncovalent complex formed by hVKORC1 and PDI was found, which is proposed to be a first precursor to probe thiol–disulphide exchange reactions between PDI and hVKORC1. Full article

(This article belongs to the Special Issue Molecular Recognition in Biological and Bioengineered Systems)

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14 pages, 4022 KiB

Open AccessArticle

Molecular Recognition of the HPLC Whelk-O1 Selector towards the Conformational Enantiomers of Nevirapine and Oxcarbazepine

by Roberta Franzini, Marco Pierini, Andrea Mazzanti, Antonia Iazzetti, Alessia Ciogli and Claudio Villani

Int. J. Mol. Sci. 2021, 22(1), 144; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22010144 - 25 Dec 2020

Cited by 7 | Viewed by 2420

Abstract

The presence of stereogenic elements is a common feature in pharmaceutical compounds, and affording optically pure stereoisomers is a frequent issue in drug design. In this context, the study of the chiral molecular recognition mechanism fundamentally supports the understanding and optimization of chromatographic [...] Read more.

The presence of stereogenic elements is a common feature in pharmaceutical compounds, and affording optically pure stereoisomers is a frequent issue in drug design. In this context, the study of the chiral molecular recognition mechanism fundamentally supports the understanding and optimization of chromatographic separations with chiral stationary phases. We investigated, with molecular docking, the interactions between the chiral HPLC selector Whelk-O1 and the stereoisomers of two bioactive compounds, the antiviral Nevirapine and the anticonvulsant Oxcarbazepine, both characterized by two stereolabile conformational enantiomers. The presence of fast-exchange enantiomers and the rate of the interconversion process were studied using low temperature enantioselective HPLC and VT-NMR with Whelk-O1 applied as chiral solvating agent. The values of the energetic barriers of interconversion indicate, for the single enantiomers of both compounds, half-lives sufficiently long enough to allow their separation only at critically sub-ambient temperatures. The chiral selector Whelk-O1 performed as a strongly selective discriminating agent both when applied as a chiral stationary phase (CSP) in HPLC and as CSA in NMR spectroscopy. Full article

(This article belongs to the Special Issue Molecular Recognition in Biological and Bioengineered Systems)

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19 pages, 4343 KiB

Open AccessArticle

Highly Efficient, Tripodal Ion-Pair Receptors for Switching Selectivity between Acetates and Sulfates Using Solid–Liquid and Liquid–Liquid Extractions

by Marta Zaleskaya, Łukasz Dobrzycki and Jan Romański

Int. J. Mol. Sci. 2020, 21(24), 9465; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21249465 - 12 Dec 2020

Cited by 9 | Viewed by 2241

Abstract

A tripodal, squaramide-based ion-pair receptor 1 was synthesized in a modular fashion, and ¹H NMR and UV-vis studies revealed its ability to interact more efficiently with anions with the assistance of cations. The reference tripodal anion receptor 2, lacking a crown [...] Read more.

A tripodal, squaramide-based ion-pair receptor 1 was synthesized in a modular fashion, and ¹H NMR and UV-vis studies revealed its ability to interact more efficiently with anions with the assistance of cations. The reference tripodal anion receptor 2, lacking a crown ether unit, was found to lose the enhancement in anion binding induced by presence of cations. Besides the ability to bind anions in enhanced manner by the “single armed” ion-pair receptor 3, the lack of multiple and prearranged binding sites resulted in its much lower affinity towards anions than in the case of tripodal receptors. Unlike with receptors 2 or 3, the high affinity of 1 towards salts opens up the possibility of extracting extremely hydrophilic sulfate anions from aqueous to organic phase. The disparity in receptor 1 binding modes towards monovalent anions and divalent sulfates assures its selectivity towards sulfates over other lipophilic salts upon liquid–liquid extraction (LLE) and enables the Hofmeister bias to be overcome. By changing the extraction conditions from LLE to SLE (solid–liquid extraction), a switch of selectivity from sulfates to acetates was achieved. X-ray measurements support the ability of anion binding by cooperation of the arms of receptor 1 together with simultaneous binding of cations. Full article

(This article belongs to the Special Issue Molecular Recognition in Biological and Bioengineered Systems)

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14 pages, 3169 KiB

Open AccessArticle

A Rational Insight into the Effect of Dimethyl Sulfoxide on TNF-α Activity

by Nasir Javaid, Mahesh Chandra Patra, Hana Seo, Farzana Yasmeen and Sangdun Choi

Int. J. Mol. Sci. 2020, 21(24), 9450; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21249450 - 11 Dec 2020

Cited by 3 | Viewed by 2254

Abstract

Direct inhibition of tumor necrosis factor-alpha (TNF-α) action is considered a promising way to prevent or treat TNF-α-associated diseases. The trimeric form of TNF-α binds to its receptor (TNFR) and activates the downstream signaling pathway. The interaction of TNF-α with molecular-grade dimethyl sulfoxide [...] Read more.

Direct inhibition of tumor necrosis factor-alpha (TNF-α) action is considered a promising way to prevent or treat TNF-α-associated diseases. The trimeric form of TNF-α binds to its receptor (TNFR) and activates the downstream signaling pathway. The interaction of TNF-α with molecular-grade dimethyl sulfoxide (DMSO) in an equal volumetric ratio renders TNF-α inert, in this state, TNF-α fails to activate TNFR. Here, we aimed to examine the inhibition of TNF-α function by various concentrations of DMSO. Its higher concentration led to stronger attenuation of TNF-α-induced cytokine secretion by fibroblasts, and of their death. We found that this inhibition was mediated by a perturbation in the formation of the functional TNF-α trimer. Molecular dynamics simulations revealed a transient interaction between DMSO molecules and the central hydrophobic cavity of the TNF-α homodimer, indicating that a brief interaction of DMSO with the TNF-α homodimer may disrupt the formation of the functional homotrimer. We also found that the sensitizing effect of actinomycin D on TNF-α-induced cell death depends upon the timing of these treatments and on the cell type. This study will help to select an appropriate concentration of DMSO as a working solvent for the screening of water-insoluble TNF-α inhibitors. Full article

(This article belongs to the Special Issue Molecular Recognition in Biological and Bioengineered Systems)

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20 pages, 3131 KiB

Open AccessArticle

Evidence for Pentapeptide-Dependent and Independent CheB Methylesterases

by Félix Velando, José A. Gavira, Miriam Rico-Jiménez, Miguel A. Matilla and Tino Krell

Int. J. Mol. Sci. 2020, 21(22), 8459; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21228459 - 11 Nov 2020

Cited by 5 | Viewed by 2265

Abstract

Many bacteria possess multiple chemosensory pathways that are composed of homologous signaling proteins. These pathways appear to be functionally insulated from each other, but little information is available on the corresponding molecular basis. We report here a novel mechanism that contributes to pathway [...] Read more.

Many bacteria possess multiple chemosensory pathways that are composed of homologous signaling proteins. These pathways appear to be functionally insulated from each other, but little information is available on the corresponding molecular basis. We report here a novel mechanism that contributes to pathway insulation. We show that, of the four CheB paralogs of Pseudomonas aeruginosa PAO1, only CheB₂ recognizes a pentapeptide at the C-terminal extension of the McpB (Aer2) chemoreceptor (K_D = 93 µM). McpB is the sole chemoreceptor that stimulates the Che2 pathway, and CheB₂ is the methylesterase of this pathway. Pectobacterium atrosepticum SCRI1043 has a single CheB, CheB_Pec, and 19 of its 36 chemoreceptors contain a C-terminal pentapeptide. The deletion of cheB_Pec abolished chemotaxis, but, surprisingly, none of the pentapeptides bound to CheB_Pec. To determine the corresponding structural basis, we solved the 3D structure of CheB_Pec. Its structure aligned well with that of the pentapeptide-dependent enzyme from Salmonella enterica. However, no electron density was observed in the CheB_Pec region corresponding to the pentapeptide-binding site in the Escherichia coli CheB. We hypothesize that this structural disorder is associated with the failure to bind pentapeptides. Combined data show that CheB methylesterases can be divided into pentapeptide-dependent and independent enzymes. Full article

(This article belongs to the Special Issue Molecular Recognition in Biological and Bioengineered Systems)

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Review

Jump to: Research, Other

34 pages, 5781 KiB

Open AccessReview

Trimethyllysine: From Carnitine Biosynthesis to Epigenetics

by Marijn N. Maas, Jordi C. J. Hintzen, Miriam R. B. Porzberg and Jasmin Mecinović

Int. J. Mol. Sci. 2020, 21(24), 9451; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21249451 - 11 Dec 2020

Cited by 18 | Viewed by 5036

Abstract

Trimethyllysine is an important post-translationally modified amino acid with functions in the carnitine biosynthesis and regulation of key epigenetic processes. Protein lysine methyltransferases and demethylases dynamically control protein lysine methylation, with each state of methylation changing the biophysical properties of lysine and the [...] Read more.

Trimethyllysine is an important post-translationally modified amino acid with functions in the carnitine biosynthesis and regulation of key epigenetic processes. Protein lysine methyltransferases and demethylases dynamically control protein lysine methylation, with each state of methylation changing the biophysical properties of lysine and the subsequent effect on protein function, in particular histone proteins and their central role in epigenetics. Epigenetic reader domain proteins can distinguish between different lysine methylation states and initiate downstream cellular processes upon recognition. Dysregulation of protein methylation is linked to various diseases, including cancer, inflammation, and genetic disorders. In this review, we cover biomolecular studies on the role of trimethyllysine in carnitine biosynthesis, different enzymatic reactions involved in the synthesis and removal of trimethyllysine, trimethyllysine recognition by reader proteins, and the role of trimethyllysine on the nucleosome assembly. Full article

(This article belongs to the Special Issue Molecular Recognition in Biological and Bioengineered Systems)

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Other

Jump to: Research, Review

32 pages, 62275 KiB

Open AccessPerspective

Aptamer-Functionalized Hybrid Nanostructures for Sensing, Drug Delivery, Catalysis and Mechanical Applications

by Margarita Vázquez-González and Itamar Willner

Int. J. Mol. Sci. 2021, 22(4), 1803; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22041803 - 11 Feb 2021

Cited by 16 | Viewed by 4714

Abstract

Sequence-specific nucleic acids exhibiting selective recognition properties towards low-molecular-weight substrates and macromolecules (aptamers) find growing interest as functional biopolymers for analysis, medical applications such as imaging, drug delivery and even therapeutic agents, nanotechnology, material science and more. The present perspective article introduces a [...] Read more.

Sequence-specific nucleic acids exhibiting selective recognition properties towards low-molecular-weight substrates and macromolecules (aptamers) find growing interest as functional biopolymers for analysis, medical applications such as imaging, drug delivery and even therapeutic agents, nanotechnology, material science and more. The present perspective article introduces a glossary of examples for diverse applications of aptamers mainly originated from our laboratory. These include the introduction of aptamer-functionalized nanomaterials such as graphene oxide, Ag nanoclusters and semiconductor quantum dots as functional hybrid nanomaterials for optical sensing of target analytes. The use of aptamer-functionalized DNA tetrahedra nanostructures for multiplex analysis and aptamer-loaded metal-organic framework nanoparticles acting as sense-and-treat are introduced. Aptamer-functionalized nano and microcarriers are presented as stimuli-responsive hybrid drug carriers for controlled and targeted drug release, including aptamer-functionalized SiO₂ nanoparticles, carbon dots, metal-organic frameworks and microcapsules. A further application of aptamers involves the conjugation of aptamers to catalytic units as a means to mimic enzyme functions “nucleoapzymes”. In addition, the formation and dissociation of aptamer-ligand complexes are applied to develop mechanical molecular devices and to switch nanostructures such as origami scaffolds. Finally, the article discusses future challenges in applying aptamers in material science, nanotechnology and catalysis. Full article

(This article belongs to the Special Issue Molecular Recognition in Biological and Bioengineered Systems)

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