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1.
J Chem Inf Model ; 60(3): 1551-1558, 2020 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-32053358

RESUMO

Intrinsically disordered proteins (IDPs) exert their functions by binding to partner proteins via a complex process that includes coupled folding and binding. Because inhibiting the binding of the IDP p53 to its partner MDM2 has become a promising strategy for the design of anticancer drugs, we carried out metadynamics simulations to study the coupled folding and binding process linking the IDP p53 to MDM2 in atomic detail. Using bias-exchange metadynamics (BE-MetaD) and infrequent metadynamics (InMetaD), we estimated the binding free energy, the unbinding rate, and the binding rate. By analyzing the stable intermediates, we uncovered the role non-native interactions played in the p53-MDM2 binding/unbinding process. We used a three-state model to describe the whole binding/unbinding process and to obtain the corresponding rate constants. Our work shows that the binding of p53 favors an induced-fit mechanism which proceeds in a stepwise fashion. Our results can be helpful for gaining an in-depth understanding of the coupled folding and binding process needed for the design of MDM2 inhibitors.

2.
ACS Appl Mater Interfaces ; 12(4): 4276-4284, 2020 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-31896256

RESUMO

Various squaraine dyes have been developed for biological imaging. Nevertheless, squaraine dyes with emission in the second window (NIR-II, 1000-1700 nm) have few reports largely due to the short of a simple and universal design strategy. In this contribution, molecular engineering strategy is explored to develop squaraine dyes with NIR-II emission. First, NIR-I squaraine dye SQ2 is constructed by the ethyl-grafted 1,8-naphtholactam as donor units and square acid as acceptor unit in a donor-acceptor-donor (D-A-D) structure. To red-shift the fluorescence emission into NIR-II window, malonitrile, as a forceful electron-withdrawing group, is introduced to strengthen square acid acceptor. As a result, the fluorescence spectrum of acceptor-engineered squaraine dye SQ1 exhibits a significant red-shift into NIR-II window. To translate NIR-II fluorophores SQ1 into effective theranostic agents, fibronectin-targeting SQ1 nanoprobe was constructed and showed excellent NIR-II imaging performance in angiography and tumor imaging, including lung metastatic foci in deep tissue. Furthermore, SQ1 nanoprobe can be used for photoacoustic imaging and photothermal ablation of tumors. This research demonstrates that the donor-acceptor engineering strategy is feasible and effective to develop NIR-II squaraine dyes.

3.
J Chem Inf Model ; 59(9): 3910-3918, 2019 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-31454236

RESUMO

Understanding unbinding kinetics of protein-ligand systems is of great importance for the design of ligands with desired specificity and safety. In recent years, enhanced sampling techniques have emerged as effective tools for studying unbinding kinetics of protein-ligand systems at the atomistic level. However, in many protein-ligand systems, the ligand unbinding processes are strongly coupled to protein conformational changes and the disclosure of the hidden degrees of freedom closely related to the protein conformational changes so that sampling is enhanced over these degrees of freedom remains a great challenge. Here, we show how potential-scaled molecular dynamics (sMD) and infrequent metadynamics (InMetaD) simulation techniques can be combined to successfully reveal the unbinding mechanism of 3-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-6-[18F]fluo-rodibenzo[b,d]thiophene 5,5-dioxide ([18F]ASEM) from a chimera structure of the α7-nicotinic acetylcholine receptor. By using sMD simulations, we disclosed that the "close" to "open" conformational change of loop C plays a key role in the ASEM unbinding process. By carrying out InMetaD simulations with this conformational change taken into account as an additional collective variable, we further captured the key states in the unbinding process and clarified the unbinding mechanism of ASEM from the protein. Our work indicates that combining sMD and InMetaD simulation techniques can be an effective approach for revealing the unbinding mechanism of a protein-ligand system where protein conformational changes control the unbinding process.

4.
ACS Chem Neurosci ; 10(3): 1783-1790, 2019 03 20.
Artigo em Inglês | MEDLINE | ID: mdl-30698013

RESUMO

The amyloid ß (Aß) fibril is a hallmark of Alzheimer's disease (AD) and has therefore served as an important target for early diagnosis of AD. The Pittsburgh Compound-B (PiB) is one of the most famous positron emission tomography (PET) tracers commonly used for in vivo detection of Aß fibrils. Many theoretical studies have predicted the existence of various core binding sites with different microenvironments for probes binding to the Aß fibril. However, little attention has been devoted to how the probes actually penetrate into the different core binding sites. In this study, an integrated molecular modeling scheme is used to study the penetration of PiB into the core binding sites of the Aß1-42 fibril structure recently obtained by cryogenic electron microscopy. We find that there are two core binding sites for PiB with dramatic differences in cavity size and microenvironment properties, and furthermore that the penetration of PiB into site-1 is energetically prohibitive, whereas the penetration into site-2 is much more favorable. Therefore, the binding capacity at site-2 may be larger than that at site-1 despite its lower binding affinity. Our results thus suggest that site-2 may be a major binding site for PiB binding to Aß fibril and emphasize the importance to adopt a full dynamical picture when studying tracer-fibril binding problems in general, something that in turn can be used to guide the development of tracers with higher affinity and selectivity for the Aß fibril.

5.
Biochemistry ; 57(18): 2606-2610, 2018 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-29638118

RESUMO

Antimicrobial peptides (AMPs) are a promising alternative to antibiotics for mitigating bacterial infections, in light of increasing bacterial resistance to antibiotics. However, predicting, understanding, and controlling the antibacterial activity of AMPs remain a significant challenge. While peptide intramolecular interactions are known to modulate AMP antimicrobial activity, peptide intermolecular interactions remain elusive in their impact on peptide bioactivity. Herein, we test the relationship between AMP intermolecular interactions and antibacterial efficacy by controlling AMP intermolecular hydrophobic and hydrogen bonding interactions. Molecular dynamics simulations and Gibbs free energy calculations in concert with experimental assays show that increasing intermolecular interactions via interpeptide aggregation increases the energy cost for the peptide to embed into the bacterial cell membrane, which in turn decreases the AMP antibacterial activity. Our findings provide a route for predicting and controlling the antibacterial activity of AMPs against Gram-negative bacteria via reductions of intermolecular AMP interactions.


Assuntos
Peptídeos Catiônicos Antimicrobianos/química , Metabolismo Energético/efeitos dos fármacos , Agregados Proteicos/efeitos dos fármacos , Peptídeos Catiônicos Antimicrobianos/metabolismo , Peptídeos Catiônicos Antimicrobianos/farmacologia , Membrana Celular/química , Membrana Celular/efeitos dos fármacos , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Negativas/patogenicidade , Humanos , Simulação de Dinâmica Molecular
6.
Chem Sci ; 8(11): 7552-7559, 2017 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-29163910

RESUMO

Peptide drugs have been difficult to translate into effective therapies due to their low in vivo stability. Here, we report a strategy to develop peptide-based therapeutic nanoparticles by screening a peptide library differing by single-site amino acid mutations of lysine-modified cholesterol. Certain cholesterol-modified peptides are found to promote and stabilize peptide α-helix formation, resulting in selectively cell-permeable peptides. One cholesterol-modified peptide self-assembles into stable nanoparticles with considerable α-helix propensity stabilized by intermolecular van der Waals interactions between inter-peptide cholesterol molecules, and shows 68.3% stability after incubation with serum for 16 h. The nanoparticles in turn interact with cell membrane cholesterols that are disproportionately present in cancer cell membranes, inducing lipid raft-mediated endocytosis and cancer cell death. Our results introduce a strategy to identify peptide nanoparticles that can effectively reduce tumor volumes when administered to in in vivo mice models. Our results also provide a simple platform for developing peptide-based anticancer drugs.

7.
ACS Sens ; 2(8): 1139-1145, 2017 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-28741347

RESUMO

Hypoxia is a common feature of tumor cells. Nitroreductase (NTR), a common biomarker of hypoxia, has been widely used to evaluate the extent of tumor hypoxia. In this study, three fluorescent probes (FBN-1-3) were synthesized to monitor the extent of hypoxia in cancer cells in real time. FBN-1-3 were composed of a fluorescein analogue and one of three different aromatic nitro groups. Of these probes, FBN-1 showed excellent sensitivity and selectivity in detecting hypoxia via a reduction in O2 concentration. Confocal fluorescence imaging and flow cytometry demonstrated that HepG-2, A549, and SKOV-3 cells incubated with FBN-1 under reduced oxygen conditions showed significantly enhanced fluorescence. A mouse HepG-2 tumor model confirmed that FBN-1 responds rapidly to NTR and can be used to evaluate the degree of tumor hypoxia. The changes in intra- and extracellular NTR in tumor cells were also concurrently monitored, which did not reveal a link between NTR concentration and degree of hypoxia. Our work provides a functional probe for tumor hypoxia, and our results suggest the fluorescent response of our probe is due to a decrease in O2 concentration, and not NTR concentration.

8.
Chem Soc Rev ; 44(15): 5200-19, 2015 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-25952028

RESUMO

Through their unique and specific interactions with various metal ions, naturally occurring proteins control structures and functions of many biological processes and functions in organisms. Inspired by natural metallopeptides, chemists have developed artificial peptides which coordinate with metal ions through their functional groups either for introducing a special reactivity or for constructing nanostructures. However, the design of new coordination peptides requires a deep understanding of the structures, assembly properties, and dynamic behaviours of such peptides. This review briefly discusses strategies of peptide self-assembly induced by metal coordination to different natural and non-natural binding sites in the peptide. The structures and functions of the obtained aggregates are described as well. We also highlight some examples of a metal-induced peptide self-assembly with relevance to biotechnology applications.


Assuntos
Complexos de Coordenação , Metais , Peptídeos , Sítios de Ligação , Bioquímica , Complexos de Coordenação/química , Complexos de Coordenação/metabolismo , Metais/química , Metais/metabolismo , Peptídeos/química , Peptídeos/metabolismo , Ligação Proteica
9.
Sci Rep ; 4: 6860, 2014 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-25358905

RESUMO

In this report, antibacterial peptides 1-3 were prepared with a spiropyran fluorescence probe. The probe exhibits a change in fluorescence when isomerized from a colorless spiro-form (spiropyran, Sp) to a colored open-form (merocyanine, Mc) under different chemical environments, which can be used to study the mechanism of antimicrobial activity. Peptides 1-3 exhibit a marked decrease in antimicrobial activity with increasing alkyl chain length. This is likely due to the Sp-Mc isomers in different polar environments forming different aggregate sizes in TBS, as demonstrated by time-dependent dynamic light scattering (DLS). Moreover, peptides 1-3 exhibited low cytotoxicity and hemolytic activity. These probe-modified peptides may provide a novel approach to study the effect of structural changes on antibacterial activity, thus facilitating the design of new antimicrobial agents to combat bacterial infection.


Assuntos
Antibacterianos/síntese química , Antibacterianos/farmacologia , Peptídeos Catiônicos Antimicrobianos/síntese química , Peptídeos Catiônicos Antimicrobianos/farmacologia , Antibacterianos/química , Peptídeos Catiônicos Antimicrobianos/química , Benzopiranos/química , Linhagem Celular , Corantes Fluorescentes/química , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Humanos , Indóis/química , Concentração Inibidora 50 , Testes de Sensibilidade Microbiana , Estrutura Molecular , Nitrocompostos/química
10.
Sci Rep ; 4: 6487, 2014 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-25270511

RESUMO

We report a novel peptide probe for the detection of neurokinin-1 receptor using disaggregation-caused signal enhancement. The probe was obtained via the aggregation of a modified substance P in a terpyridine-Fe (II) complex with Gd (III)-DOTA into well-defined nanostructures, which effectively weaken ligand fluorescence and slow the exchange rate of inner-sphere water molecules. This probe disaggregates upon binding to the neurokinin-1 receptor and activates the contrast agents to generate a fluorescent signal that positively enhances magnetic resonance imaging contrast and allows for the detection of overexpressed receptors on tumor cells and the identification of lung cancer using serum samples.


Assuntos
Meios de Contraste , Gadolínio , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/metabolismo , Imagem por Ressonância Magnética/métodos , Fragmentos de Peptídeos , Receptores da Neurocinina-1/metabolismo , Biomarcadores/análise , Proliferação de Células , Citometria de Fluxo , Fluorescência , Humanos , Células Tumorais Cultivadas
11.
Nanoscale ; 6(24): 14772-83, 2014 Dec 21.
Artigo em Inglês | MEDLINE | ID: mdl-25355048

RESUMO

Polydiacetylene (PDA) micelles have been widely used to deliver anticancer drugs in the treatment of a variety of tumours and for imaging living cells. In this study, we developed an effective strategy to directly conjugate magainin II (MGN-II) to the surface of PDA micelles using a fluorescent dye. These stable and well-defined PDA micelles had high cytotoxicity in cancer cell lines, and were able to reduce the tumour size in mice. The modified PDA micelles improved the anticancer effects of MGN-II in the A549 cell line only at a concentration of 16.0 µg mL(-1) (IC50). In addition, following irradiation with UV light at 254 nm, the PDA micelles gave rise to an energy transfer from the fluorescent dye to the backbone of PDA micelles to enhance the imaging of living cells. Our results demonstrate that modified PDA micelles can not only be used in the treatment of tumors in vitro and in vivo in a simple and directed way, but also offer a new platform for designing functional liposomes to act as anticancer agents.


Assuntos
Magaininas/administração & dosagem , Nanocápsulas/química , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/patologia , Polímeros/química , Poli-Inos/química , Proteínas de Xenopus/administração & dosagem , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Difusão , Desenho de Drogas , Corantes Fluorescentes/química , Magaininas/química , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Micelas , Microscopia de Fluorescência/métodos , Nanocápsulas/administração & dosagem , Nanocápsulas/ultraestrutura , Tamanho da Partícula , Polímero Poliacetilênico , Resultado do Tratamento , Proteínas de Xenopus/química
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