| 1. |
- Kuang, Guanglin, et al.
(författare)
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Characterization of the binding mode of the PET tracer [18F]ASEM to a chimera structure of the α7 nicotinic acetylcholine receptor
- 2017
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Ingår i: RSC Advances. - : Royal Society of Chemistry. - 2046-2069. ; 7:32, s. 19787-19793
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Tidskriftsartikel (refereegranskat)abstract
- The α7 nicotinic acetylcholine receptor (α7-nAChR) is assumed to be implicated in a variety of neurological disorders, such as schizophrenia and Alzheimer's disease (AD). The progress of these disorders can be studied through imaging α7-nAChR with positron emission tomography (PET). [18F]ASEM is a novel and potent α7-nAChR PET radioligand showing great promise in recent tests. However, the mechanism of the molecular interaction between [18F]ASEM and α7-nAChR is still unclear. In this paper, the binding profile of [18F]ASEM to a chimera structure of α7-nAChR was investigated with molecular docking, molecular dynamics, and metadynamics simulation methods. We found that [18F]ASEM binds at the same site as the crystallized agonist epibatidine but with a different binding mode. The dibenzo[b,d]thiophene ring has a different orientation compared to the pyridine ring of epibatidine and has van der Waals interactions with residues from loop C on one side and π-π stacking interaction with Trp53 on the other side. The conformation of Trp53 was found to have a great impact on the binding of [18F]ASEM. Six binding modes in terms of the side chain dihedral angles χ1 and χ2 of Trp53 were discovered by metadynamics simulation. In the most stable binding mode, Trp53 adopts a different conformation from that in the crystalline structure and has a rather favorable π-π stacking interaction with [18F]ASEM. We believe that these discoveries can be valuable for the development of novel PET radioligands.
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| 2. |
- Li, Junhao, et al.
(författare)
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Exploring the Interactions between two Ligands, UCB-J and UCB-F, and Synaptic Vesicle Glycoprotein 2 Isoforms
- 2024
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Ingår i: ACS Chemical Neuroscience. - : American Chemical Society (ACS). - 1948-7193. ; 15:10, s. 2018-2027
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Tidskriftsartikel (refereegranskat)abstract
- In silico modeling was applied to study the efficiency of two ligands, namely, UCB-J and UCB-F, to bind to isoforms of the synaptic vesicle glycoprotein 2 (SV2) that are involved in the regulation of synaptic function in the nerve terminals, with the ultimate goal to understand the selectivity of the interaction between UCB-J and UCB-F to different isoforms of SV2. Docking and large-scale molecular dynamics simulations were carried out to unravel various binding patterns, types of interactions, and binding free energies, covering hydrogen bonding and nonspecific hydrophobic interactions, water bridge, π–π, and cation−π interactions. The overall preference for bonding types of UCB-J and UCB-F with particular residues in the protein pockets can be disclosed in detail. A unique interaction fingerprint, namely, hydrogen bonding with additional cation−π interaction with the pyridine moiety of UCB-J, could be established as an explanation for its high selectivity over the SV2 isoform A (SV2A). Other molecular details, primarily referring to the presence of π–π interactions and hydrogen bonding, could also be analyzed as sources of selectivity of the UCB-F tracer for the three isoforms. The simulations provide atomic details to support future development of new selective tracers targeting synaptic vesicle glycoproteins and their associated diseases.
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| 3. |
- Li, S., et al.
(författare)
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Cholesterol-directed nanoparticle assemblies based on single amino acid peptide mutations activate cellular uptake and decrease tumor volume
- 2017
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Ingår i: Chemical Science. - : Royal Society of Chemistry. - 2041-6520 .- 2041-6539. ; 8:11, s. 7552-7559
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 4. |
- Luo, Shenzheng, et al.
(författare)
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A Probe for the Detection of Hypoxic Cancer Cells
- 2017
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Ingår i: ACS Sensors. - : AMER CHEMICAL SOC. - 2379-3694. ; 2:8, s. 1139-1145
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Tidskriftsartikel (refereegranskat)abstract
- 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 O-2 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 O-2 concentration, and not NTR concentration.
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| 5. |
- Yao, Defan, et al.
(författare)
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Molecular Engineered Squaraine Nanoprobe for NIR-II/Photoacoustic Imaging and Photothermal Therapy of Metastatic Breast Cancer
- 2020
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Ingår i: ACS Applied Materials and Interfaces. - : American Chemical Society (ACS). - 1944-8244 .- 1944-8252. ; 12:4, s. 4276-4284
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 6. |
- Zhan, Shaoqi, et al.
(författare)
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Dynamics with Explicit Solvation Reveals Formation of the Prereactive Dimer as Sole Determining Factor for the Efficiency of Ru(bda)L-2 Catalysts
- 2018
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Ingår i: ACS Catalysis. - : AMER CHEMICAL SOC. - 2155-5435 .- 2155-5435. ; 8:9, s. 8642-8648
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Tidskriftsartikel (refereegranskat)abstract
- This report describes all key steps in the O-O bond formation from two separated [Ru-V=O(bda)L-2](+) cations to form the dinuclear [(bda)L2RuIV-O-Ru-IV(bda)L-2](2+) in explicit solvent. The three steps involve the diffusion of the catalysts in the water phase, formation of the prereactive dimer, and the bond formation between the two catalysts. On the basis of the calculated parameters, we compute the rate constant of two catalysts with different L-ligands, isoquinoline and picoline, and the computed values are in excellent agreement with the experimental ones. The interaction of the axial ligands is key to the improved rates of the larger ligand, mainly by facilitating the formation of the prereactive dimer from the solvated monomer. By comparing the binding free energy of hydrophilic Ru-IV-OH and hydrophobic Ru-V=O, the hydrophobic driving force of Ru-V=O in this system has been estimated to 1 kcal mol(-1).
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| 7. |
- Zhou, Yang, 1986-, et al.
(författare)
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Enhanced Sampling Simulations of Ligand Unbinding Kinetics Controlled by Protein Conformational Changes
- 2019
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Ingår i: Journal of Chemical Information and Modeling. - : AMER CHEMICAL SOC. - 1549-9596 .- 1549-960X. ; 59:9, s. 3910-3918
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Tidskriftsartikel (refereegranskat)abstract
- 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-[F-18]fluorodibenzo[b,d]thiophen e 5,5-dioxide ([F-18]ASEM) from a chimera structure of the alpha 7-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.
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| 8. |
- Zhu, X., et al.
(författare)
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A supramolecular peptide polymer from hydrogen-bond and coordination-driven self-assembly
- 2018
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Ingår i: Polymer Chemistry. - : Royal Society of Chemistry. - 1759-9954 .- 1759-9962. ; 9:1, s. 69-76
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Tidskriftsartikel (refereegranskat)abstract
- A terpyridine- and guanine-functionalized peptide was developed that could form different morphologies by self-assembly or coordination with Fe2+ in dimethyl sulfoxide. The self-assembly of the peptide is attributed to the G-quartet formation of a guanine moiety and intermolecular terpyridine π-π stacking. Upon the addition of Fe2+, a Fe2+-(terpyridine)2 complex is formed that turns the square-planar self-assembly to a three-dimensional self-assembly. As a consequence, a variety of interesting morphologies and chemical properties were observed. The self-assembled polymers were studied by nuclear magnetic resonance spectroscopy, ultraviolet-visible and fluorescence spectroscopy, viscosity measurement, circular dichroism, Fourier transform infrared spectroscopy, X-ray diffraction, scanning electron microscopy, transmission electron microscopy, dynamic light scattering, and atomic force microscopy. This external stimuli driven self-assembly of a peptide may be further applied to drug delivery applications.
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| 9. |
- Zou, Rongfeng, et al.
(författare)
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Activity of Antimicrobial Peptide Aggregates Decreases with Increased Cell Membrane Embedding Free Energy Cost
- 2018
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Ingår i: Biochemistry. - : AMER CHEMICAL SOC. - 0006-2960 .- 1520-4995. ; 57:18, s. 2606-2610
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 10. |
- Zou, Rongfeng, et al.
(författare)
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An Efficient Strategy for the Estimation of Rare Event Transition Times in Biomolecular Systems
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Studies of kinetics in biological systems are important for understanding functions of biomolecules and can provide valuable information for drug discovery. However, how to obtain the kinetics closely related to a rare event occurring in a biomolecular system from conventional unbiased molecular dynamics (MD) simulations remains a big challenge. Recently, an enhanced sampling method, namely infrequent metadynamics (InMetaD), has been developed and has the capability to recover the unbiased transition time from metadynamic runs. However, in this method a bias potential is deposited to the system at a low frequency, which often makes most of the computational time spend in waiting for the simulated system escaping from the initial state. Here we propose a strategy to achieve the same goal as InMetaD with increased efficiency. In this strategy, we first accelerate the occurring of a rare event using metadynamics simulations with a high bias deposition frequency, and subsequently restart the simulations at a time point before the rare event occurs, but with a low bias deposition frequency. Through combining these simulation data, the unbiased transition time can be recovered in the same way as in InMetaD. We applied this strategy to the studies of three systems including the conformational change of a small peptide, unfolding of a protein, and unbinding of an intrinsically disordered protein from its target. We show that our strategy can improve the efficiency in estimating the unbiased transition times in a very convenient way.
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