The Au clusters induce tumor cell apoptosis via specifically targeting thioredoxin reductase 1 (TrxR1) and suppressing its activity

Liu, Ru; Wang, Yaling; Yuan, Qing; An, Deyi; Li, Jingyuan; Gao, Xueyun

doi:10.1039/c4cc03320e

Cited by 54 publications

(84 citation statements)

References 28 publications

(8 reference statements)

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“…As indicated by our previous work 38 , the peptide-coated AuNC interrogated here can effectively inhibit the activity of TrxR1 in the cytoplasm. We now study the binding of this AuNC to TrxR1 and investigate any prevailing modes of interaction between the enzyme and nanoparticle that might emerge.…”

Section: The Binding Process Of Aunc To Trxr1 In Solutionsupporting

confidence: 59%

“…In our system, the Au 25 cluster is coated by nine tridecapeptides (sequence CCYGGPKKKRKVG). 38 In preparation for our initial TrxR1-free simulations, the coated AuNC was solvated in a cubic box with a dimension of 104 Å. Requisite numbers of sodium and chloride ions were then added to neutralize the system and to achieve a physiological ionic concentration of 150 mM; AuNC configurations were also studied in a solution of low ionic strength, to which only 45 chloride ions were added to neutralize the system. 51,52 The mineralization sequence CCY (coupled to a GG linker) was added to the N-terminus of the NLS sequence: the dicysteine motif serves to anchor the tridecapeptides directly to the gold cluster center.…”

Section: System and Methodologymentioning

confidence: 99%

“…Several gold-containing compounds have been designed to inhibit the activity of TrxR1, leveraging coordination between gold atoms and the SH/SeH groups in the active site of TrxR1 35, 36 . Interestingly, this peptide-coated gold nanocluster (AuNC) has been shown to effectively bind and inhibit TrxR1, inducing tumor cell apoptosis in a dose dependent manner 38 . Recently, our collaborators synthesized a peptide-coated gold nanocluster, Au 25 peptide 9 , comprised of a 25 gold atom-core coated with nine tridecapeptides 37 .…”

Section: Introductionmentioning

confidence: 99%

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A Peptide-Coated Gold Nanocluster Exhibits Unique Behavior in Protein Activity Inhibition

Weber

et al. 2015

J. Am. Chem. Soc.

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Gold nanoclusters (AuNCs) can be primed for biomedical applications through functionalization with peptide coatings. Often anchored by thiol groups, such peptide coronae not only serve as passivators but can also endow AuNCs with additional bioactive properties. In this work, we use molecular dynamics simulations to study the structure of a tridecapeptide-coated Au25 cluster and its subsequent interactions with the enzyme thioredoxin reductase 1, TrxR1. We find that, in isolation, both the distribution and conformation of the coating peptides fluctuate considerably. When the coated AuNC is placed around TrxR1, however, the motion of the highly charged peptide coating (+5e/peptide) is quickly biased by electrostatic attraction to the protein; the asymmetric coating acts to guide the nanocluster's diffusion toward the enzyme's negatively charged active site. After the AuNC comes into contact with TrxR1, its peptide corona spreads over the protein surface to facilitate stable binding with protein. Though individual salt bridge interactions between the tridecapeptides and TrxR1 are transient in nature, the cooperative binding of the peptide-coated AuNC is very stable, overall. Interestingly, the biased corona peptide motion, the spreading and the cooperation between peptide extensions observed in AuNC binding are reminiscent of bacterial stimulus-driven approaching and adhesion mechanisms mediated by cilia. The prevailing AuNC binding mode we characterize also satisfies a notable hydrophobic interaction seen in the association of thioredoxin to TrxR1, providing a possible explanation for the AuNC binding specificity observed in experiments. Our simulations thus suggest this peptide-coated AuNC serves as an adept thioredoxin mimic that extends an array of auxiliary structural components capable of enhancing interactions with the target protein in question.

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Section: The Binding Process Of Aunc To Trxr1 In Solutionsupporting

confidence: 59%

Section: System and Methodologymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

A Peptide-Coated Gold Nanocluster Exhibits Unique Behavior in Protein Activity Inhibition

Weber

et al. 2015

J. Am. Chem. Soc.

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“…Evidence of interactions between thioredoxin reductase and nanoclusters composed of 25 gold atoms stabilized by a tridecapeptide has also been reported [64]. The positively charged peptide enhanced the solubility of the gold clusters, and also facilitated electrostatic binding interactions with a number of negatively charged amino acid residues near the active site of the enzyme.…”

Section: Thioredoxin Reductase Binding Studiesmentioning

confidence: 88%

An investigation into the interactions of gold nanoparticles and anti-arthritic drugs with macrophages, and their reactivity towards thioredoxin reductase

James

Sluyter

et al. 2015

Journal of Inorganic Biochemistry

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“…[20][21][22][23][24][25] Recently, a peptide coated AuNC was designed to specifically target the cell nuclei of different cell lines with red fluorescence emission. 28 The atomic structures of peptide coated AuNCs are critical for their applications in protein targeting, by means of which one can further clarify their specific interaction mechanisms. 27 One tridecapeptide coated AuNC could penetrate the cell membrane and target the TrxR enzyme in cytosol to suppress its activity and further cause tumor cell apoptosis.…”

Section: Introductionmentioning

confidence: 99%

Atomic structure of a peptide coated gold nanocluster identified using theoretical and experimental studies

Wang

Gao

et al. 2016

Nanoscale

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Peptide coated gold nanoclusters (AuNCs) have a precise molecular formula and atomic structure, which are critical for their unique applications in targeting specific proteins either for protein analysis or drug design. To date, a study of the crystal structure of peptide coated AuNCs is absent primarily due to the difficulty of obtaining their crystalline phases in an experiment. Here we study a typical peptide coated AuNC (Au24Peptide8, Peptide = H2N-CCYKKKKQAGDV-COOH, Anal. Chem., 2015, 87, 2546) to figure out its atomic structure and electronic structure using a theoretical method for the first time. In this work, we identify the explicit configuration of the essential structure of Au24Peptide8, Au24(Cys-Cys)8, using density functional theory (DFT) computations and optical spectroscopic experiments, where Cys denotes cysteine without H bonded to S. As the first multidentate ligand binding AuNC, Au24(Cys-Cys)8 is characterized as a distorted Au13 core with Oh symmetry covered by two Au(Cys-Cys) and three Au3(Cys-Cys)2 staple motifs in its atomic structure. The most stable configuration of Au24(Cys-Cys)8 is confirmed by comparing its UV-vis absorption spectrum from time-dependent density-functional theory (TDDFT) calculations with optical absorption measurements, and these results are consistent with each other. Furthermore, we carry out frontier molecular orbital (FMO) calculations to elucidate that the electronic structure of Au24(Cys-Cys)8 is different from that of Au24(SR)20 as they have a different Au/S ratio, where SR represents alkylthiolate. Importantly, the different ligand coatings, Cys-Cys and SR, in Au24(Cys-Cys)8 and Au24(SR)20 cause the different Au/S ratios in the coated Au24. The reason is that the Au/S ratio is crucial in determining the size of the Au core of the ligand protected AuNC, and the size of the Au core corresponds to a specific electronic structure. By the adjustment of ligand coatings from alkylthiolate to peptide, the Au/S ratio could be controlled to generate different AuNCs with versatile electronic structures, optical properties and reaction stabilities. Therefore, we propose a universal approach to obtain a specific Au/S ratio of ligand coated AuNCs by adjusting the ligand composition, thus controlling the chemicophysical properties of AuNCs with ultimately the same number of Au atoms.

show abstract

The Au clusters induce tumor cell apoptosis via specifically targeting thioredoxin reductase 1 (TrxR1) and suppressing its activity

Cited by 54 publications

References 28 publications

A Peptide-Coated Gold Nanocluster Exhibits Unique Behavior in Protein Activity Inhibition

A Peptide-Coated Gold Nanocluster Exhibits Unique Behavior in Protein Activity Inhibition

An investigation into the interactions of gold nanoparticles and anti-arthritic drugs with macrophages, and their reactivity towards thioredoxin reductase

Atomic structure of a peptide coated gold nanocluster identified using theoretical and experimental studies

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