| 1. |
- Fu, Y., et al.
(författare)
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Defect-Assisted Loading and Docking Conformations of Pharmaceuticals in Metal–Organic Frameworks
- 2021
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Ingår i: Angewandte Chemie International Edition. - : Wiley. - 1433-7851 .- 1521-3773. ; 60:14, s. 7719-7727
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Tidskriftsartikel (refereegranskat)abstract
- Understanding of drug–carrier interactions is essential for the design and application of metal–organic framework (MOF)-based drug-delivery systems, and such drug–carrier interactions can be fundamentally different for MOFs with or without defects. Herein, we reveal that the defects in MOFs play a key role in the loading of many pharmaceuticals with phosphate or phosphonate groups. The host–guest interaction is dominated by the Coulombic attraction between phosphate/phosphonate groups and defect sites, and it strongly enhances the loading capacity. For similar molecules without a phosphate/phosphonate group or for MOFs without defects, the loading capacity is greatly reduced. We employed solid-state NMR spectroscopy and molecular simulations to elucidate the drug–carrier interaction mechanisms. Through a synergistic combination of experimental and theoretical analyses, the docking conformations of pharmaceuticals at the defects were revealed.
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| 2. |
- Li, Jiachen, et al.
(författare)
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A combined computational and experimental approach predicts thrombin adsorption to zeolites
- 2023
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Ingår i: Colloids and Surfaces B. - : Elsevier BV. - 0927-7765 .- 1873-4367. ; 221, s. 113007-
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Tidskriftsartikel (refereegranskat)abstract
- Robust protein-nanomaterial surface analysis is important, but also a challenge. Thrombin plays an important role in the coagulant activity of protein corona mediated by Ca2+ ion exchanged zeolites. However, the mech-anism for this modulation remains unresolved. In this study, we proposed a combined computational and experimental approach to determine the adsorbed sites and orientations of thrombin binding to Ca2+-exchanged LTA-type (CaA) zeolite. Specifically, fourteen ensembles of simulated annealing molecular dynamics (SAMD) simulations and experimental surface residues microenvironment analysis were used to reduce the starting orientations needed for further molecular dynamics (MD) simulations. The combined MD simulations and pro -coagulant activity characterization also reveal the consequent corresponding deactivation of thrombin on CaA zeolite. It is mainly caused by two aspects: (1) the secondary structure of thrombin can change after its adsorption on the CaA zeolite. (2) The positively charged area of thrombin mediates the preferential interaction between thrombin and CaA zeolite. Some thrombin substrate sites are thus blocked by zeolite after its adsorption. This study not only provides a promising method for characterizing the protein-nanoparticle interaction, but also gives an insight into the design and application of zeolite with high procoagulant activity.
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| 3. |
- Li, Jiachen, et al.
(författare)
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Binding modes of prothrombin cleavage site sequences to the factor Xa catalytic triad : Insights from atomistic simulations
- 2022
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Ingår i: Computational and Structural Biotechnology Journal. - : Elsevier BV. - 2001-0370. ; 20, s. 5401-5408
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Tidskriftsartikel (refereegranskat)abstract
- Prothrombin is a key zymogen of the coagulation process and can be converted to thrombin by the prothrombinase complex, which consists of factor Xa (FXa), cofactor Va (FVa), and phospholipids. Prothrombin can be activated at two cleavage sites, R271 and R320, which generates two intermediates: prethrombin-2 via the initial cleavage at R271, and meizothrombin via the first cleavage at R320. Several mechanisms have been proposed to explain this activation preference, but the role of cleavage site sequences in prothrombin activation has not been thoroughly investigated. Here, we used an advanced sampling technique, parallel tempering metadynamics with a well-tempered ensemble (PTMetaDWTE), to study the binding modes of prothrombin cleavage site sequences R266AIEGRTATSEY277 (denoted as Pep271) and S315YIDGRIVEGSD326 (denoted as Pep320) to the FXa catalytic triad. Our study indicates that there exist three binding modes for Pep271 to the FXa catalytic triad but only one binding mode for Pep320 to the FXa catalytic triad. Further molecular dynamics simulations revealed that due to the strong electrostatic interactions, especially the H-bond interactions and salt bridges formed between Pep320 and FXa, the binding mode in the Pep320-FXa system is more stable than the binding modes in the Pep271-FXa system. In view of experimental observations and our results that there exists only one binding mode for Pep320 to the FXa catalytic triad and especially R320 in Pep320 can stably bind to the FXa catalytic triad, we believe that the first cleavage at R320 is favored.
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| 4. |
- Li, Junhao, et al.
(författare)
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Dissecting the Structural Plasticity and Dynamics of Cytochrome P450 2B4 by Molecular Dynamics Simulations
- 2020
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Ingår i: Journal of Chemical Information and Modeling. - : American Chemical Society (ACS). - 1549-9596 .- 1549-960X. ; 60:10, s. 5026-5035
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Tidskriftsartikel (refereegranskat)abstract
- The plasticity of cytochromes P450 (P450s) is known to contribute significantly to their catalytic capacity of metabolizing various substrates. Although numerous studies have been performed, factors governing the plasticity and dynamics of P450s are still not fully understood. In this study, taking CYP2B4 as an example, we dissect the protein plasticity and dynamics in different environments. CYP2B4 is featured by a high degree of plasticity, which exhibits open, closed, and intermediate states. By analyzing the CYP2B4 crystal structures, we identified the structural features for the closed, open, and intermediate states. Interestingly, formation of the dimer structure was found in the open and intermediate states. The subsequent molecular dynamics (MD) simulations of the open structure in water confirmed the importance of the dimer form in stabilizing the open conformations. MD simulations of the closed and open structures in the membrane environment and the free energies for opening the F-G cassette obtained from the umbrella sampling calculations indicate that the membrane environment is important for stabilizing the F-G cassette. The dynamical network analysis indicates that Asp105 on the B-C loop plays an important role in transiting the structure from the open to the intermediate state. Our results thus unveil the mechanisms of dimer formation and open-to-intermediate transition for CYP2B4 in the water and membrane environments.
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| 5. |
- Li, Junhao, et al.
(författare)
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Homotropic Cooperativity of Midazolam Metabolism by Cytochrome P450 3A4 : Insight from Computational Studies
- 2021
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Ingår i: Journal of Chemical Information and Modeling. - : American Chemical Society (ACS). - 1549-9596 .- 1549-960X. ; 61:5, s. 2418-2426
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Tidskriftsartikel (refereegranskat)abstract
- Human cytochrome P450 3A4 (CYP3A4) is responsible for the metabolism of similar to 50% clinically used drugs. Midazolam (MDZ) is a commonly used sedative drug and serves as a marker substrate for the CYP3A4 activity assessment. MDZ is metabolized by CYP3A4 to two hydroxylation products, 1'-OH-MDZ and 4-OH-MDZ. It has been reported that the ratio of 1'-OH-MDZ and 4-OH-MDZ is dependent on the MDZ concentration, which reflects the homotropic cooperative behavior in MDZ metabolism by CYP3A4. Here, we used quantum chemistry (QC), molecular docking, conventional molecular dynamics (cMD), and Gaussian accelerated molecular dynamics (GaMD) approaches to investigate the mechanism of the interactions between CYP3A4 and MDZ. QC calculations suggest that C1' is less reactive for hydroxylation than C4, which is a pro-chirality carbon. However, the 4-OH-MDZ product is likely to be racemic due to the chirality inversion in the rebound step. The MD simulation results indicate that MDZ at the peripheral allosteric site is not stable and the binding modes of the MDZ molecules at the productive site are in line with the experimental observations.
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| 6. |
- Li, Junhao, 1989-, et al.
(författare)
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Mechanistic Insights into the Regio‐ and Stereoselectivities of Testosterone and Dihydrotestosterone Hydroxylation Catalyzed by CYP3A4 and CYP19A1
- 2020
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Ingår i: Chemistry - A European Journal. - Weinheim, Germany : Wiley. - 0947-6539 .- 1521-3765. ; 26:28, s. 6214-6223
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Tidskriftsartikel (refereegranskat)abstract
- The hydroxylation of nonreactive C−H bonds can be easily catalyzed by a variety of metalloenzymes, especially cytochrome P450s (P450s). The mechanism of P450 mediated hydroxylation has been intensively studied, both experimentally and theoretically. However, understanding the regio‐ and stereoselectivities of substrates hydroxylated by P450s remains a great challenge. Herein, we use a multi‐scale modeling approach to investigate the selectivity of testosterone (TES) and dihydrotestosterone (DHT) hydroxylation catalyzed by two important P450s, CYP3A4 and CYP19A1. For CYP3A4, two distinct binding modes for TES/DHT were predicted by dockings and molecular dynamics simulations, in which the experimentally identified sites of metabolism of TES/DHT can access to the catalytic center. The regio‐ and stereoselectivities of TES/DHT hydroxylation were further evaluated by quantum mechanical and ONIOM calculations. For CYP19A1, we found that sites 1β, 2β and 19 can access the catalytic center, with the intrinsic reactivity 2β>1β>19. However, our ONIOM calculations indicate that the hydroxylation is favored at site 19 for both TES and DHT, which is consistent with the experiments and reflects the importance of the catalytic environment in determining the selectivity. Our study unravels the mechanism underlying the selectivity of TES/DHT hydroxylation mediated by CYP3A4 and CYP19A1 and is helpful for understanding the selectivity of other substrates that are hydroxylated by P450s.
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| 7. |
- Li, Junhao, 1989-
(författare)
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Theoretical Studies of Drug-Metabolizing Cytochrome P450 Enzymes
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The family of cytochrome P450 enzymes (P450s) belongs to one of the most important enzyme families in the human body. P450s are involved in the synthesis of endogenous compounds and metabolism of exogenous substances. In mammalian species, drug metabolizing P450s are anchored in the bilayer lipid membrane, which allows the enzymes to interact with other proteins and ligand molecules. A wealth of knowledge about the structures, functions, and mechanisms of P450s have been obtained from both experimental and theoretical studies. However, the mechanisms behind some experimental results, such as the regio- and stereoselectivity and structural flexibility are still elusive.In this thesis, I present the work done in my doctoral studies, which was focused on the catalytic selectivity and structural flexibility of P450s. Multiple theoretical modeling approaches, such as homology modeling, molecular docking, molecular dynamics, quantum mechanics, and quantum mechanics/molecular mechanics, were applied in the studies. In papers I and II, the regio- and stereoselectivity of CYP4F2, CYP3A4, and CYP19A1 catalyzed C–H hydroxylation of different substrates were studied. The results indicate that the ligand reactivity and accessibility can be decisive for the regio- and stereoselectivity. However, which of them is more important is system-dependent. The quantum mechanics/molecular mechanics calculation results imply that the distribution of spin natural orbitals could be used for discriminating the roles of the reactivity and accessibility. In papers III and IV, the conformational dynamics of the open and closed structures of CYP2B4 and the ligand cooperativity phenomenon of midazolam metabolized by CYP3A4 were investigated using molecular dynamics simulations. From the simulation results, we identified the key residues for the conformational dynamics for the open-to-intermediate transition and found that the ligand cooperativity is also caused by the large flexibility of P450. The results also indicated that the homotropic cooperativity mainly occurs in the large and flexible productive site, rather than in the remote allosteric site.
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| 8. |
- Nag, S., et al.
(författare)
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Development of 11C-Labeled ASEM Analogues for the Detection of Neuronal Nicotinic Acetylcholine Receptors (α7-nAChR)
- 2022
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Ingår i: ACS Chemical Neuroscience. - : American Chemical Society (ACS). - 1948-7193. ; 13:3, s. 352-362
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Tidskriftsartikel (refereegranskat)abstract
- The homo-pentameric alpha 7 receptor is one of the major types of neuronal nicotinic acetylcholine receptors (α7-nAChRs) related to cognition, memory formation, and attention processing. The mapping of α7-nAChRs by PET pulls a lot of attention to realize the mechanism and development of CNS diseases such as AD, PD, and schizophrenia. Several PET radioligands have been explored for the detection of the α7-nAChR. 18F-ASEM is the most functional for in vivo quantification of α7-nAChRs in the human brain. The first aim of this study was to initially use results from in silico and machine learning techniques to prescreen and predict the binding energy and other properties of ASEM analogues and to interpret these properties in terms of atomic structures using 18F-ASEM as a lead structure, and second, to label some selected candidates with carbon-11/hydrogen-3 (11C/3H) and to evaluate the binding properties in vitro and in vivo using the labeled candidates. In silico predictions are obtained from perturbation free-energy calculations preceded by molecular docking, molecular dynamics, and metadynamics simulations. Machine learning techniques have been applied for the BBB and P-gp-binding properties. Six analogues of ASEM were labeled with 11C, and three of them were additionally labeled with 3H. Binding properties were further evaluated using autoradiography (ARG) and PET measurements in non-human primates (NHPs). Radiometabolites were measured in NHP plasma. All six compounds were successfully synthesized. Evaluation with ARG showed that 11C-Kln83 was preferably binding to the α7-nAChR. Competition studies showed that 80% of the total binding was displaced. Further ARG studies using 3H-KIn-83 replicated the preliminary results. In the NHP PET study, the distribution pattern of 11C-KIn-83 was similar to other α7 nAChR PET tracers. The brain uptake was relatively low and increased by the administration of tariquidar, indicating a substrate of P-gp. The ASEM blocking study showed that 11C-KIn-83 specifically binds to α7 nAChRs. Preliminary in vitro evaluation of KIn-83 by ARG with both 11C and 3H and in vivo evaluation in NHP showed favorable properties for selectively imaging α7-nAChRs, despite a relatively low brain uptake.
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| 9. |
- Teng, Dan, et al.
(författare)
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Mechanistic Studies on the Stereoselectivity of FFAR1 Modulators
- 2022
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Ingår i: Journal of Chemical Information and Modeling. - : American Chemical Society (ACS). - 1549-9596 .- 1549-960X. ; 62:15, s. 3664-3675
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Tidskriftsartikel (refereegranskat)abstract
- Free fatty acid receptor 1 (FFAR1) is a potential therapeutic target for the treatment of type 2 diabetes (T2D). It has been validated that agonists targeting FFAR1 can achieve the initial therapeutic endpoints of T2D, and the epimer agonists (R,S) AM-8596 can activate FFAR1 differently, with one acting as a partial agonist and the other as a full agonist. Up to now, the origin of the stereoselectivity of FFAR1 agonists remains elusive. In this work, we used molecular simulation methods to elucidate the mechanism of the stereoselectivity of the FFAR1 agonists (R)-AM-8596 and (S)-AM-8596. We found that the full agonist (R)-AM-8596 disrupts the residue interaction network around the receptor binding pocket and promotes the opening of the binding site for the G-protein, thereby resulting in the full activation of FFAR1. In contrast, the partial agonist (S)-AM-8596 forms stable electrostatic interactions with FFAR1, which stabilizes the residue network and hinders the conformational transition of the receptor. Our work thus clarifies the selectivity and underlying molecular activation mechanism of FFAR1 agonists.
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| 10. |
- Wang, Yamin, et al.
(författare)
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Reductive Decomposition of Solvents and Additives toward Solid-Electrolyte Interphase Formation in Lithium-Ion Battery
- 2020
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Ingår i: The Journal of Physical Chemistry C. - : American Chemical Society (ACS). - 1932-7447 .- 1932-7455. ; 124:17, s. 9099-9108
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Tidskriftsartikel (refereegranskat)abstract
- The solid-electrolyte interphase (SEI) formed through the reductive decomposition of solvent molecules plays a crucial role in the stability and durability of lithium-ion batteries. Here, we investigate the initial process of SEI formation through reactive force field-molecular dynamics (ReaxFF-MD) simulations and density functional theory (DFT) calculations. ReaxFF-MD is used as a simulation protocol to predict the evolution of SEI components, and products are obtained in good agreement with the experimental results. DFT calculations are then used to model the reaction center. We find that one-electron reduction induces the similar breaking of the C-O bond in solvent ethylene carbonate (EC) and additive fluoroethylene carbonate (FEC). When another electron is added, EC decomposition produces gas CO + alkylcarbonate or ethylene (C2H4) + carbonate (CO32-), whereas FEC decomposition generates lithium fluoride (LiF) and vinylene carbonate (VC) in addition to CO + alkylcarbonate. LiF and VC could also be regarded as important electrolyte additives to improve battery performance. The reduction on FEC moiety/molecule is more energetically favorable than that on the corresponding EC moiety/molecule. This knowledge on the decomposition products at the atomic scale well correlate with available experiments, and theory provides useful guidelines and structural motifs for interpretations of future SEI-related experiments.
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| 11. |
- Zhao, Yihao, et al.
(författare)
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Sigmoid Accelerated Molecular Dynamics : An Efficient Enhanced Sampling Method for Biosystems
- 2023
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Ingår i: The Journal of Physical Chemistry Letters. - : American Chemical Society (ACS). - 1948-7185. ; 14:4, s. 1103-1112
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Tidskriftsartikel (refereegranskat)abstract
- Gaussian accelerated molecular dynamics (GaMD) is recognized as a popular enhanced sampling method for tackling long-standing challenges in biomolecular simulations. Inspired by GaMD, Sigmoid accelerated molecular dynamics (SaMD) is proposed in this work by adding a Sigmoid boost potential to improve the balance between the highest acceleration and accurate reweighting. Compared with GaMD, SaMD extends the accessible time scale and improves the computational efficiency as tested in three tasks. In the alanine dipeptide task, SaMD can produce the free energy landscape with better accuracy and efficiency. In the chignolin folding task, the estimated Gibbs free energy difference can converge to the experimental value ∼30% faster. In the protein-ligand binding task, the bound conformations are closer to the crystal structure with a minimal ligand root-mean-square deviation of 1.7 Å. The binding of the ligand XK263 to the HIV protease is reproduced by SaMD in ∼60% less simulation time.
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| 12. |
- Zhengzhong, Kang, 1990-
(författare)
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Understanding Defect Structures and Host-guest Interactions in Metal-organic Frameworks
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Metal-organic frameworks (MOFs) represent a class of crystalline porous materials with prospective applications in molecular capture, separation, storage and catalysis. It has been discovered that there exist various structural defects in MOFs, which can have dramatic impact on their properties. However, the fundamental understanding of the structure and chemistry of the defects in MOFs is still very limited.In this thesis, I focus on the studies of defect structures and host-guest interactions in MOFs by using theoretical chemistry methods. These studies cover the dynamic interplay of water and acetate molecules at the defect sites of linker missing MOFs, host-guest interactions of drug molecules loading in defective MOFs, preparation and triggered release of intrinsically coordinated CpG-MOF conjugate nanoparticles, and the defect-assisted single-strand DNA adsorption and folding on MOFs. The main results of the studies are described below.1. The possible binding structure of acetate and water molecules on defect sites in MOFs are explored. Acetate is coordinated to an unsaturated metal site in a monodentate way, which is accompanied by a water molecule coordinated to the neighboring metal site. The highly flexible acetate molecule performs a fast rotation and undergoes a slow kinetic exchange with a water molecule. Two models, one with insufficient water and the other with excess water, were built to study the role of dynamic hydrogen bonds in the exchange process.2. The loading behavior of drug molecules in MOFs has been studied. The interactions between the drugs and MOFs are fundamentally different for the ideal and defective MOFs. The defects play a key role in the loading of the drugs with phosphate or phosphonate groups on MOFs. The host-guest interactions are dominated by the Coulombic attraction between the phosphate/phosphonate groups and the defect sites, which greatly enhances the loading capacity of the drugs. The conformations of the drugs at the defect sites have also been studied. 3. A new strategy for preparing DNA-MOF conjugates is provided and the interactions between oligonucleotides and MOFs have been studied. Compared to the covalent modification of DNA-MOF nanoparticles, the unmodified oligonucleotides can be densely loaded on the MOFs via the intrinsic, multivalent coordination of the DNA backbone phosphate to the unsaturated zirconium sites on the MOFs. The loading state of CpG on the MOFs is the coexistence of nucleotides in the adsorption state and dangling state. The surface-bound DNA can be efficiently released by free phosphate ions in the acidic environment. 4. The loading and folding of ssDNA on MOFs have been systematically studied. ssDNA prefers to be on the surface of the MOFs rather than inside a cage due to size limitation. The defect-assisted surface adsorption is mainly contributed by the electrostatic interactions between the ssDNA and MOFs. The binding of the ssDNA to the MOFs is dominated by the multiple point anchoring of the phosphate groups of the ssDNA on the MOF clusters. Water layers with complex hydrogen-bond network function as a gate, preventing the DNA from approaching the MOFs before adsorption and inhibiting the DNA from leaving the MOFs after anchoring. Unlike the circular folding structure in the solution, the adsorbed ssDNA display a slender conformation or duplex like structure.
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| 13. |
- Zhou, Yang, et al.
(författare)
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In silico studies of ASEM analogues targeting alpha 7-nAChR and experimental verification
- 2021
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Ingår i: RSC Advances. - : ROYAL SOC CHEMISTRY. - 2046-2069. ; 11:7, s. 3942-3951
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Tidskriftsartikel (refereegranskat)abstract
- The alpha 7 nicotinic acetylcholine receptor (alpha 7-nAChR) is implicated in a variety of neurodegenerative and neuropsychiatric disorders, such as Alzheimer's disease (AD) and schizophrenia. The progress of these disorders can be studied using positron emission tomography (PET) with radiotracers for alpha 7-nAChR. [F-18]ASEM and [F-18] para-ASEM (also referred to as [F-18]DBT-10) are novel and potent alpha 7-nAChR PET radiotracers which have successfully been used in human subjects and nonhuman primates, though further improvement of them is still a pressing task in the community of neurodegeneration research. In this work, we demonstrate the use of modern in silico techniques to predict the binding modes, binding strengths, and residence times for molecular PET tracers binding to proteins, using ASEM and DBT-10 as a showcase of the predictive and interpretational power of such techniques, in particular free energy perturbation theory. The corresponding compounds were synthesized and further tested by in vitro binding experiment for validation. Encouragingly, our in silico modeling can correctly predict the binding affinities of the ASEM analogues. The structure-activity relationships for the ortho- and para-substitutions are well explained at the atomistic level and provide structure-based guiding for the future development of PET tracers for alpha 7-nAChR. A discussion is presented on the complementary use of in silico rational methods based on atomic and electronic principles for in vitro characterization of PET tracers.
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| 14. |
- Zhou, Yang, 1989-
(författare)
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Modeling Kinetics of Protein-Ligand Systems
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Protein-ligand interactions dominate many life activities and are crucial for thedevelopment of tracers for diagnosing diseases and drugs for treating diseases.For protein-ligand interactions, the binding affinity is conventionally believedto be the most important indicator. However, there is increasing evidencethat the binding affinity alone is not sufficient for providing comprehensiveinformation about protein-ligand interactions. Kinetics, which describes theduration of the interactions and is closely related to the interaction mechanism,is considered as important as, or even more important than, the binding affinityin the study of the mechanisms of protein-ligand interactions.Although kinetics parameters of a protein-ligand system can be measuredexperimentally, the underlying molecular mechanism for the kinetics is difficultto reveal by experiment, which is, however, essential for understanding theorigin of the kinetics and for the rational design of drugs or tracers. In the lastdecade, computer simulations have emerged as a powerful tool for studying biomolecularsystems. Computer simulation methods have also been developedfor modeling kinetics of protein-ligand systems.In this thesis, I explored computer simulations for modeling kinetics propertiesof four different protein-ligand systems. In paper I, I studied the relationshipbetween the ligand binding and conformational changes of the ATAD2-BRD protein. In paper II, I investigated the free energy profile for the coupledfolding and binding of the intrinsically disordered protein p53 with MDM2and calculated the rate constants for the binding and unbinding processes. Inpaper III, I revealed the unbinding paths of the PET tracer ASEM from the a7-nAChR, calculated the unbinding rate, and explored a way of how to findthe key protein conformational changes strongly coupled to the ligand unbindingprocess. In paper IV, I further refined our methodology for finding theunbinding paths and clarified the unbinding mechanism of the metabolite ofraloxifene from the enzyme CYP3A4.
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| 15. |
- Zhou, Yang, 1989-, et al.
(författare)
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Unraveling the Abnormal Molecular Mechanism of Suicide Inhibition of Cytochrome P450 3A4
- 2022
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Ingår i: Journal of Chemical Information and Modeling. - : American Chemical Society (ACS). - 1549-9596 .- 1549-960X. ; 62:23, s. 6172-6181
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Tidskriftsartikel (refereegranskat)abstract
- Suicide inhibition of the CYP3A4 enzyme by a drug inactivates the enzyme in the drug biotransformation process and often shows safety concerns about the drug. Despite extensive experimental studies, the abnormal molecular mechanism of a suicide inhibitor that forms a covalent bond with the residue far away from the catalytically active center of CYP3A4 inactivating the enzyme remains elusive. Here, the authors used molecular simulation approaches to study in detail how diquinone methide (DQR), the metabolite product of raloxifene, unbinds from CYP3A4 and inactivates the enzyme at the atomistic level. The results dearly indicate that in one of the intermediate states formed in its unbinding process, DQR covalently binds to Cys239, a residue far away from the catalytically active center of CYP3A4, and hinders the substrate from entering or leaving the enzyme. This work therefore provides an unprecedented way of clarifying the abnormal mechanism of suicide inhibition of the CYP3A4 enzyme.
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| 16. |
- Zou, Rongfeng, et al.
(författare)
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Free Energy Profile and Kinetics of Coupled Folding and Binding of the Intrinsically Disordered Protein p53 with MDM2
- 2020
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Ingår i: Journal of Chemical Information and Modeling. - : American Chemical Society (ACS). - 1549-9596 .- 1549-960X. ; 60:3, s. 1551-1558
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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