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Journal ArticleDOI: 10.1002/CBIC.202000581

Programmed and Sequential Disassembly of Multi-responsive Supramolecular Protein Nanoassemblies: A Detailed Mechanistic Investigation

02 Mar 2021-ChemBioChem (Wiley)-Vol. 22, Iss: 5, pp 876-887
Abstract: The rational design of a multi-responsive protein-based supramolecular system that can predictably respond to more than one stimulus remains an essential but highly challenging goal in biomolecular engineering. Herein, we report a novel chemical method for the construction of multi-responsive supramolecular nanoassemblies using custom-designed facially amphiphilic monodisperse protein-dendron bioconjugates. The macromolecular synthons contain a globular hydrophilic protein domain site-specifically conjugated to photo-responsive hydrophobic benzyl-ether dendrons of different generations through oligo(ethylene glycol) linkers of defined length. The size of the protein nanoassemblies can be systematically tuned by choosing an appropriate dendron or linker of defined length. Exposure of protein nanoassemblies to light results in partial rather than complete disassembly of the complex. The newly formed protein nanoparticle no longer responds to light but could be disassembled into constitutive monomers under acidic conditions or by further treatment with a small molecule. More interestingly, the distribution ratio of the assembled versus disassembled states of protein nanoassemblies after photochemical reaction does not depend on dendron generation, the nature of the linker functionality or the identity of the protein, but is heavily influenced by the linker length. In sum, this work discloses a new chemical method for the rational design of a monodisperse multi-responsive protein-based supramolecular system with exquisite control over the disassembly process.

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Topics: Rational design (52%), Dendrimer (50%)

7 results found

Open accessJournal Article
Christopher N. Lam1, Bradley D. Olsen1Institutions (1)
Abstract: The phase behaviour of mCherry-b-PNIPAM (mChP) block copolymers with four different PNIPAM coil fractions is investigated in concentrated aqueous solution as a function of both concentration and temperature, demonstrating both order–order transitions (OOTs) and order–disorder transitions (ODTs) in globular protein–polymer block copolymers. Independent of coil volume fraction from 0.25 to 0.70, the temperature–concentration phase diagrams share several common features. At low concentrations, mCherry-b-PNIPAM forms a homogeneous disordered phase, and macrophase separation into an ordered conjugate-rich phase and a solvent-rich phase is observed at temperatures above the PNIPAM thermoresponsive transition temperature. mChP solutions are also observed to undergo a low-temperature ODT driven by increasing concentration. The order–disorder transition concentration (ODTC) behaviour of mChP is minimized for symmetric conjugates, suggesting that repulsive solvent-mediated protein–polymer interactions provide a driving force for self-assembly. Both coil fraction and solvent selectivity have large effects on the morphologies formed—disordered micelles, hexagonally packed cylinders, lamellae, and perforated lamellae are identified with the combination of small-angle X-ray scattering (SAXS), depolarized light scattering (DPLS), turbidimetry, and differential scanning calorimetry (DSC). An OOT is observed upon increasing temperature for three of the studied coil fractions at concentrations of 40–50 wt% due to changing solvent selectivity. SANS contrast-matching experiments show that water is weakly selective for PNIPAM at low temperatures and strongly selective for mCherry at high temperatures.

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49 Citations

Open accessJournal ArticleDOI: 10.1002/CBIC.202100288
13 Oct 2021-ChemBioChem
Abstract: The reversible nature of disulfide functionality has been exploited to design intelligent materials such as nanocapsules, micelles, vesicles, inorganic nanoparticles, peptide and nucleic acid nanodevices. Herein, we report a new chemical methodology for the construction redox-sensitive protein assemblies using monodisperse facially amphiphilic protein-dendron bioconjugates. The disulfide functionality is strategically placed between the dendron and protein domains. The custom designed bioconjugates self-assembled into nanoscopic objects of a defined size dictated by the nature of dendron domain. The stimuli-responsive behavior of the protein assemblies is demonstrated using a suitable redox trigger.

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Topics: Dendrimer (51%), Rational design (50%)

1 Citations

Open accessJournal ArticleDOI: 10.1002/CBIC.202100315
03 Nov 2021-ChemBioChem
Abstract: Self-assembly of a monomeric protease to form a multi-subunit protein complex "proteasome" enables targeted protein degradation in living cells. Naturally occurring proteasomes serve as an inspiration and blueprint for the design of artificial protein-based nanoreactors. Here we disclose a general chemical strategy for the design of proteasome-like nanoreactors. Micelle-assisted protein labeling (MAPLab) technology along with the N-terminal bioconjugation strategy is utilized for the synthesis of a well-defined monodisperse self-assembling semi-synthetic protease. The designed protein is programmed to self-assemble into a proteasome-like nanostructure which preserves the functional properties of native protease.

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Topics: Protein degradation (60%), Rational design (52%), Bioconjugation (50%)

1 Citations

Open accessPosted ContentDOI: 10.1101/2021.08.01.454616
02 Aug 2021-bioRxiv
Abstract: Self-assembling artificial proteins (SAPs) have gained enormous interest in recent years due to their applications in different fields. Synthesis of well-defined monodisperse SAPs is accomplished predominantly through genetic methods. However, the last decade witnessed the use of few chemical technologies for that purpose. In particular, micelle-assisted protein labeling technology (MAPLabTech) has made huge progress in this area. The first generation MAPLabTech focused on site-specific labeling of the active-site residue of serine proteases to make SAPs. Further, this methodology was exploited for labeling of N-terminal residue of a globular protein to make functional SAPs. In this study, we describe the synthesis of novel SAPs by developing a chemical method for site-specific labeling of a surface-exposed cysteine residue of globular proteins. In addition, we disclose the synthesis of redox- and pH-sensitive SAPs and their systematic self-assembly and dis-assembly studies using complementary biophysical studies. Altogether these studies further expand the scope of MAPLabTech in different fields such as vaccine design, targeted drug delivery, diagnostic imaging, biomaterials, and tissue engineering.

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Open accessJournal ArticleDOI: 10.1002/CHEM.202102589
Abstract: This review presents precisely defined amphiphilic dendrons, their self-association properties, and their different uses. Dendrons, also named dendritic wedges, are composed of a core having two different types of functions, of which one type is used for growing or grafting branched arms, generally multiplied by 2 at each layer by using 1→2 branching motifs. A large diversity of structures has been already synthesized. In practically all cases, their synthesis is based on the synthesis of known dendrimers, such as poly(aryl ether), poly(amidoamine) (in particular PAMAM), poly(amide) (in particular poly(L-lysine)), 1→3 branching motifs (instead of 1→2), poly(alkyl ether) (poly(glycerol) and poly(ethylene glycol)), poly(ester), and those containing main group elements (poly(carbosilane) and poly(phosphorhydrazone)). In most cases, the hydrophilic functions are on the surface of the dendrons, whereas one or two hydrophobic tails are linked to the core. Depending on the structure of the dendrons, and on the experimental conditions used, the amphiphilic dendrons can self-associate at the air-water interface, or form micelles (eventually tubular, but most generally spherical), or form vesicles. These associated dendrons are suitable for the encapsulation of low-molecular or macromolecular bioactive entities to be delivered in cells. This review is organized depending on the nature of the internal structure of the amphiphilic dendrons (aryl ether, amidoamine, amide, quaternary carbon atom, alkyl ether, ester, main group element). The properties issued from their self-associations are described all along the review.

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Topics: Dendrimer (54%), Ether (51%), Branching (polymer chemistry) (50%)


83 results found

Journal ArticleDOI: 10.1038/NMAT3776
01 Nov 2013-Nature Materials
Abstract: Spurred by recent progress in materials chemistry and drug delivery, stimuli-responsive devices that deliver a drug in spatial-, temporal- and dosage-controlled fashions have become possible. Implementation of such devices requires the use of biocompatible materials that are susceptible to a specific physical incitement or that, in response to a specific stimulus, undergo a protonation, a hydrolytic cleavage or a (supra)molecular conformational change. In this Review, we discuss recent advances in the design of nanoscale stimuli-responsive systems that are able to control drug biodistribution in response to specific stimuli, either exogenous (variations in temperature, magnetic field, ultrasound intensity, light or electric pulses) or endogenous (changes in pH, enzyme concentration or redox gradients).

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Topics: Nanocarriers (55%), Drug delivery (55%), Drug carrier (54%)

4,033 Citations

Open accessJournal ArticleDOI: 10.1295/POLYMJ.17.117
Donald A. Tomalia1, H. Baker1, James R Dewald1, Michael B. Hall1  +5 moreInstitutions (1)
01 Jan 1985-Polymer Journal
Abstract: This paper describes the first synthesis of a new class of topological macromolecules which we refer to as “starburst polymers.” The fundamental building blocks to this new polymer class are referred to as “dendrimers.” These dendrimers differ from classical monomers/oligomers by their extraordinary symmetry, high branching and maximized (telechelic) terminal functionality density. The dendrimers possess “reactive end groups” which allow (a) controlled moelcular weight building (monodispersity), (b) controlled branching (topology), and (c) versatility in design and modification of the terminal end groups. Dendrimer synthesis is accomplished by a variety of strategies involving “time sequenced propagation” techniques. The resulting dendrimers grow in a geometrically progressive fashion as shown: Chemically bridging these dendrimers leads to the new class of macromolecules—”starburst polymers” (e.g., (A)n, (B)n, or (C)n).

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Topics: Poly(amidoamine) (59%), Dendrimer (54%)

3,153 Citations

Open accessJournal ArticleDOI: 10.1038/NATURE01406
Nadrian C. Seeman1Institutions (1)
23 Jan 2003-Nature
Abstract: The specific bonding of DNA base pairs provides the chemical foundation for genetics. This powerful molecular recognition system can be used in nanotechnology to direct the assembly of highly structured materials with specific nanoscale features, as well as in DNA computation to process complex information. The exploitation of DNA for material purposes presents a new chapter in the history of the molecule.

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Topics: DNA origami (63%), DNA nanotechnology (57%), Base pair (54%) ... read more

2,363 Citations

Journal ArticleDOI: 10.1126/SCIENCE.268.5218.1728
Lifeng Zhang1, Adi Eisenberg1Institutions (1)
23 Jun 1995-Science
Abstract: The observation by transmission electron microscopy of six different stable aggregate morphologies is reported for the same family of highly asymmetric polystyrene-poly-(acrylic acid) block copolymers prepared in a low molecular weight solvent system. Four of the morphologies consist of spheres, rods, lamellae, and vesicles in aqueous solution, whereas the fifth consists of simple reverse micelle-like aggregates. The sixth consists of up to micrometer-size spheres in aqueous solution that have hydrophilic surfaces and are filled with the reverse micelle-like aggregates. In addition, a needle-like solid, which is highly birefringent, is obtained on drying of aqueous solutions of the spherical micelles. This range of morphologies is believed to be unprecedented for a block copolymer system.

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Topics: Crew cut (53%), Aqueous solution (52%), Acrylic acid (52%) ... read more

2,206 Citations

Journal ArticleDOI: 10.1021/JA00177A027
Abstract: The novel convergent growth approach to topological macromolecules based on dendritic fragments is described. The polyether dendritic fragments are prepared by starting from what will become the periphery of the molecule and progressing inward. In the first step, 2 mol of a benzylic bromide is condensed with the two phenolic groups of the monomer, 3,5-di-hydroxybenzyl alcohol, under phase-transfer conditions. After transformation of the benzylic alcohol functionality of the growing molecule into the corresponding bromide, the procedure is repeated with stepwise addition of the monomer followed again by activation of the benzylic site. After several generations of growth, the resulting dendritic wedges, in their benzylic bromide form, can be coupled to a polyfunctional core such as 1,1,1-tris(4{prime}-hydroxyphenyl)ethane to form the final hyperbranched macromolecule. Unique features of the convergent approach include the control over the nature and placement of the groups that are placed at the periphery of the molecule and the fact that each growth step only involves reaction at a single site of the growing macromolecule.

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Topics: Macromolecule (51%)

2,142 Citations

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