Two-tier supramolecular encapsulation of small molecules in a protein cage

Abstract Expanding protein design to include other molecular building blocks has the potential to increase structural complexity and practical utility. Nature often employs hybrid systems, such as clathrin-coated vesicles, lipid droplets, and lipoproteins, which combine biopolymers and lipids to transport a broader range of cargo molecules. To recapitulate the structure and function of such composite compartments, we devised a supramolecular strategy that enables porous protein cages to encapsulate poorly water-soluble small molecule cargo through templated formation of a hydrophobic surfactant-based core. These lipoprotein-like complexes protect their cargo from sequestration by serum proteins and enhance the cellular uptake of fluorescent probes and cytotoxic drugs. This design concept could be applied to other protein cages, surfactant mixtures, and cargo molecules to generate unique hybrid architectures and functional capabilities.

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A Molecular Artisans Guide to Supramolecular Coordination Complexes and Metal Organic Frameworks

Journal of Molecular and Engineering Materials ◽

10.1142/s2251237315400043 ◽

2015 ◽

Vol 03 (01n02) ◽

pp. 1540004 ◽

Cited By ~ 2

Author(s):

Xialu Wu ◽

David J. Young ◽

T. S. Andy Hor

Keyword(s):

Chemical Reactivity ◽

Metal Organic Frameworks ◽

Building Blocks ◽

Coordination Complexes ◽

Large Molecules ◽

Molecular Building Blocks ◽

Supramolecular Coordination ◽

Metal Organic ◽

Molecular Synthesis ◽

And Function

As molecular synthesis advances, we are beginning to learn control of not only the chemical reactivity (and function) of molecules, but also of their interactions with other molecules. It is this basic idea that has led to the current explosion of supramolecular science and engineering. Parallel to this development, chemists have been actively pursuing the design of very large molecules using basic molecular building blocks. Herein, we review the general development of supramolecular chemistry and particularly of two new branches: supramolecular coordination complexes (SCCs) and metal organic frameworks (MOFs). These two fields are discussed in detail with typical examples to illustrate what is now possible and what challenges lie ahead for tomorrow's molecular artisans.

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Molecular engineering of myosin

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.2004.1565 ◽

2004 ◽

Vol 359 (1452) ◽

pp. 1907-1912 ◽

Cited By ~ 14

Author(s):

K. C. Holmes ◽

D. R. Trentham ◽

R. Simmons ◽

Dietmar J. Manstein

Keyword(s):

Protein Engineering ◽

Protein Design ◽

Catalytic Efficiency ◽

Building Blocks ◽

Structural Features ◽

Molecular Engineering ◽

Actin Binding ◽

Myosin Motor ◽

Nucleotide Binding Sites ◽

Molecular Building Blocks

Protein engineering and design provide excellent tools to investigate the principles by which particular structural features relate to the mechanisms that underlie the biological function of a protein. In addition to studies aimed at dissecting the communication pathways within enzymes, recent advances in protein engineering approaches make it possible to generate enzymes with increased catalytic efficiency and specifically altered or newly introduced functions. Here, two approaches using state–of–the–art protein design and engineering are described in detail to demonstrate how key features of the myosin motor can be changed in a specific and predictable manner. First, it is shown how replacement of an actin–binding surface loop with synthetic sequences, whose flexibility and charge density is varied, can be employed to manipulate the actin affinity, the catalytic activity and the efficiency of coupling between actin– and nucleotide–binding sites of myosin motor constructs. Then the use of pre–existing molecular building blocks, which are derived from unrelated proteins, is described for manipulating the velocity and even the direction of movement of recombinant myosins.

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Case history of porphyrin J-aggregates: a personal point of view

Journal of Porphyrins and Phthalocyanines ◽

10.1142/s1088424609000632 ◽

2009 ◽

Vol 13 (04n05) ◽

pp. 461-470 ◽

Cited By ~ 9

Author(s):

Joaquim Crusats ◽

Zoubir El-Hachemi ◽

Carlos Escudero ◽

Josep M. Ribó

Keyword(s):

Supramolecular Chemistry ◽

Self Assembly ◽

Building Blocks ◽

Point Of View ◽

Water Soluble ◽

The Self ◽

Molecular Building Blocks ◽

History Of ◽

J Aggregates ◽

The University

The formation and structure of the title aggregates are paradigms of the self-assembly of amphiphilic molecular building blocks in supramolecular chemistry. This review summarizes the research in the University of Barcelona on the homoassociation of the water soluble meso 4-sulfonatophenyl-and phenyl substituted porphyrins.

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Designed for life: biocompatible de novo designed proteins and components

Journal of The Royal Society Interface ◽

10.1098/rsif.2018.0472 ◽

2018 ◽

Vol 15 (145) ◽

pp. 20180472 ◽

Cited By ~ 8

Author(s):

Katie J. Grayson ◽

J. L. Ross Anderson

Keyword(s):

Protein Design ◽

De Novo ◽

Building Blocks ◽

De Novo Design ◽

Biochemical Processes ◽

Designed Proteins ◽

De Novo Protein Design ◽

Protein Molecules ◽

And Function

A principal goal of synthetic biology is the de novo design or redesign of biomolecular components. In addition to revealing fundamentally important information regarding natural biomolecular engineering and biochemistry, functional building blocks will ultimately be provided for applications including the manufacture of valuable products and therapeutics. To fully realize this ambitious goal, the designed components must be biocompatible, working in concert with natural biochemical processes and pathways, while not adversely affecting cellular function. For example, de novo protein design has provided us with a wide repertoire of structures and functions, including those that can be assembled and function in vivo . Here we discuss such biocompatible designs, as well as others that have the potential to become biocompatible, including non-protein molecules, and routes to achieving full biological integration.

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Genomic and physiological analyses of the zebrafish atrioventricular canal reveal molecular building blocks of the secondary pacemaker region

Cellular and Molecular Life Sciences ◽

10.1007/s00018-021-03939-y ◽

2021 ◽

Author(s):

Karim Abu Nahia ◽

Maciej Migdał ◽

T. Alexander Quinn ◽

Kar-Lai Poon ◽

Maciej Łapiński ◽

...

Keyword(s):

Epithelial To Mesenchymal Transition ◽

Fluorescent Protein ◽

Building Blocks ◽

Transgenic Zebrafish ◽

Loss Of Function ◽

Atrioventricular Canal ◽

Protein Coding ◽

Mesenchymal Transition ◽

Molecular Building Blocks ◽

And Function

AbstractThe atrioventricular canal (AVC) is the site where key structures responsible for functional division between heart regions are established, most importantly, the atrioventricular (AV) conduction system and cardiac valves. To elucidate the mechanism underlying AVC development and function, we utilized transgenic zebrafish line sqet31Et expressing EGFP in the AVC to isolate this cell population and profile its transcriptome at 48 and 72 hpf. The zebrafish AVC transcriptome exhibits hallmarks of mammalian AV node, including the expression of genes implicated in its development and those encoding connexins forming low conductance gap junctions. Transcriptome analysis uncovered protein-coding and noncoding transcripts enriched in AVC, which have not been previously associated with this structure, as well as dynamic expression of epithelial-to-mesenchymal transition markers and components of TGF-β, Notch, and Wnt signaling pathways likely reflecting ongoing AVC and valve development. Using transgenic line Tg(myl7:mermaid) encoding voltage-sensitive fluorescent protein, we show that abolishing the pacemaker-containing sinoatrial ring (SAR) through Isl1 loss of function resulted in spontaneous activation in the AVC region, suggesting that it possesses inherent automaticity although insufficient to replace the SAR. The SAR and AVC transcriptomes express partially overlapping species of ion channels and gap junction proteins, reflecting their distinct roles. Besides identifying conserved aspects between zebrafish and mammalian conduction systems, our results established molecular hallmarks of the developing AVC which underlies its role in structural and electrophysiological separation between heart chambers. This data constitutes a valuable resource for studying AVC development and function, and identification of novel candidate genes implicated in these processes.

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The contractile proteins of skeletal muscle

Proceedings of the Royal Society of London Series B Biological Sciences ◽

10.1098/rspb.1964.0053 ◽

1964 ◽

Vol 160 (981) ◽

pp. 437-441 ◽

Cited By ~ 7

Keyword(s):

Skeletal Muscle ◽

Indirect Evidence ◽

Molecular Size ◽

Building Blocks ◽

Water Soluble ◽

Fibrous Proteins ◽

Size And Shape ◽

Molecular Building Blocks ◽

Intact Muscle ◽

Almost All

The study of the molecular size and shape of the fibrous proteins isolated from skeletal muscle has an interest in its own right: but in addition it has a particular importance in that these proteins are believed to provide the ultimate molecular ‘building blocks’ for the contractile system of living muscle. Myosin, actin and tropomyosin (‘water-soluble tropomyosin’, or ‘tropomyosin B ') together comprise almost all the fraction of soluble, fibrous proteins isolated from muscle. Whilst it is possible that certain proteins present only in very small amounts, such as ∆-proteins (Amberson, White, Bensunan, Himmelfarb & Blankenhorn 1957), meta-myosin (Raeber, Schapira & Dreyfus 1955) and extra-protein (Perry 1953), may play a significant role in contraction, there is as yet no positive evidence to indicate that this is the case. In the intact muscle, the location of myosin and actin in the A -band filaments and I -band filaments has been established (Hanson & Huxley 1953). The location of tropomyosin is less certain: indirect evidence strongly suggests that it plays a part in the structure of the Z -membrane (Huxley 1963). In the present paper, the size and shape of these three molecular species, as determined in monodisperse solution, and by electron microscopy, will be discussed.

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Solubilization of Itraconazole by Surfactants and Phospholipid-Surfactant Mixtures: Interplay of Amphiphile Structure, pH and Electrostatic Interactions

10.26434/chemrxiv.12038682 ◽

2020 ◽

Author(s):

Zahari Vinarov ◽

Gabriela Gancheva ◽

Nikola Burdzhiev ◽

Slavka S. Tcholakova

Keyword(s):

Nmr Spectroscopy ◽

Electrostatic Interactions ◽

Triazole Ring ◽

Water Soluble ◽

Single Chain ◽

Surfactant Mixtures ◽

Solubilization Capacity ◽

Water Soluble Drugs ◽

Hydrophobic Chain ◽

Brick Dust

Although surfactants are frequently used in enabling formulations of poorly water-soluble drugs, the link between their structure and drug solubilization capacity is still unclear. We studied the solubilization of the “brick-dust” molecule itraconazole by 16 surfactants and 3 phospholipid:surfactant mixtures. NMR spectroscopy was used to study in more details the drug-surfactant interactions. Very high solubility of itraconazole (up to 3.6 g/L) was measured in anionic surfactant micelles at pH = 3, due to electrostatic attraction between the oppositely charged (at this pH) drug and surfactant molecules. <sup>1</sup>H NMR spectroscopy showed that itraconazole is ionized at two sites (2+ charge) at these conditions: in the phenoxy-linked piperazine nitrogen and in the dioxolane-linked triazole ring. The increase of amphiphile hydrophobic chain length had a markedly different effect, depending on the amphiphile type: the solubilization capacity of single-chain surfactants increased, whereas a decrease was observed for double-chained surfactants (phosphatidylglycerols). The excellent correlation between the chain melting temperatures of phosphatidylglycerols and itraconazole solubilization illustrated the importance of hydrophobic chain mobility. This study provides rules for selection of itraconazole solubilizers among classical single-chain surfactants and phospholipids. The basic physics underpinning the described effects suggests that these rules should be transferrable to other “brick-dust” molecules.

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A First Principles Approach for Partitioning Linear Response Properties into Additive and Cooperative Contributions

10.26434/chemrxiv.5773968.v1 ◽

2018 ◽

Cited By ~ 1

Author(s):

Daniel Lambrecht ◽

Eric Berquist

Keyword(s):

First Principles ◽

Linear Response ◽

Building Blocks ◽

Field Method ◽

Response Property ◽

Response Properties ◽

Consistent Field ◽

Molecular Building Blocks ◽

Self Consistent ◽

Self Consistent Field

We present a first principles approach for decomposing molecular linear response properties into orthogonal (additive) plus non-orthogonal/cooperative contributions. This approach enables one to 1) identify the contributions of molecular building blocks like functional groups or monomer units to a given response property and 2) quantify cooperativity between these contributions. In analogy to the self consistent field method for molecular interactions, SCF(MI), we term our approach LR(MI). The theory, implementation and pilot data are described in detail in the manuscript and supporting information.

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