| 1. |
- Tu, Guangde, et al.
(författare)
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Core electron chemical shifts of hydrogen-bonded structures
- 2009
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Ingår i: Chemical Physics Letters. - Amsterdam : Elsevier BV. - 0009-2614 .- 1873-4448. ; 468:4-6, s. 294-298
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Tidskriftsartikel (refereegranskat)abstract
- We examine the possibility to study hydrogen-bonded structures through core ionization energies. We use a recently derived self-interaction corrected density functional theory method where the core ionization energies for all chemically shifted elements are obtained by a single calculation of the ground state of the structures. A direct dependency between the hydrogen atom to acceptor atom bond length and the chemical shift of the core ionization energy of the acceptor atom is found, something that has rami. cations for the possibility of effective predictions of hydrogen bond lengths in hydrogen-bonded systems. This observation is verified by the conventional, much more time-consuming, self-consistent field calculations based on density functional theory.
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| 2. |
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| 3. |
- Brown, Christian, et al.
(författare)
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Structural and functional characterization of the microtubule interacting and trafficking domains of two oomycete chitin synthases
- 2016
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Ingår i: The FEBS Journal. - : Wiley. - 1742-464X .- 1742-4658. ; 283:16, s. 3072-3088
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Tidskriftsartikel (refereegranskat)abstract
- Chitin synthases (Chs) are responsible for the synthesis of chitin, a key structural cell wall polysaccharide in many organisms. They are essential for growth in certain oomycete species, some of which are pathogenic to diverse higher organisms. Recently, a Microtubule Interacting and Trafficking (MIT) domain, which is not found in any fungal Chs, has been identified in some oomycete Chs proteins. Based on experimental data relating to the binding specificity of other eukaryotic MIT domains, there was speculation that this domain may be involved in the intracellular trafficking of Chs proteins. However, there is currently no evidence for this or any other function for the MIT domain in these enzymes. To attempt to elucidate their function, MIT domains from two Chs enzymes from the oomycete Saprolegnia monoica were cloned, expressed and characterized. Both were shown to interact strongly with the plasma membrane component phosphatidic acid, and to have additional putative interactions with proteins thought to be involved in protein transport and localization. Aiding our understanding of these data, the structure of the first MIT domain from a carbohydrate-active enzyme (MIT1) was solved by NMR, and a model structure of a second MIT domain (MIT2) was built by homology modelling. Our results suggest a potential function for these MIT domains in the intracellular transport and/or regulation of Chs enzymes in the oomycetes.
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| 4. |
- Cheng, J., et al.
(författare)
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Molecular switches of the κ opioid receptor triggered by 6′-GNTI and 5′-GNTI
- 2016
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Ingår i: Scientific Reports. - : Nature Publishing Group. - 2045-2322. ; 6
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Tidskriftsartikel (refereegranskat)abstract
- The κ opioid receptor (κOR) is a member of G-protein-coupled receptors, and is considered as a promising drug target for treating neurological diseases. κOR selective 6′-GNTI was proved to be a G-protein biased agonist, whereas 5′-GNTI acts as an antagonist. To investigate the molecular mechanism of how these two ligands induce different behaviors of the receptor, we built two systems containing the 5′-GNTI-κOR complex and the 6′-GNTI-κOR complex, respectively, and performed molecular dynamics simulations of the two systems. We observe that transmembrane (TM) helix 6 of the κOR rotates about 4.6° on average in the κOR-6′-GNTI complex. Detailed analyses of the simulation results indicate that E2976.58 and I2946.55 play crucial roles in the rotation of TM6. In the simulation of the κOR-5′-GNTI system, it is revealed that 5′-GNTI can stabilize TM6 in the inactive state form. In addition, the kink of TM7 is stabilized by a hydrogen bond between S3247.47 and the residue V691.42 on TM1.
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| 5. |
- Feng, Yanli, et al.
(författare)
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A supramolecular photoswitch constructed by intermolecular hydrogen bond between BTEPy and TTF-COOH
- 2008
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Ingår i: Chemical Physics Letters. - : Elsevier BV. - 0009-2614 .- 1873-4448. ; 455:4-6, s. 256-260
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Tidskriftsartikel (refereegranskat)abstract
- A novel supramolecular photoswitch containing bisthienylethene- pyridine (BTEPy) and carboxyl attached tetrathiafluvalene (TTF-COOH) was constructed via intermolecular hydrogen bond. FT-IR spectra, XPS characterizations, H-1 NMR and theoretical calculation were carried out to verify the formation of the intermolecular hydrogen bond. The supramolecular self-assemblies BTEPy 2TTF show good photo-chromic properties. A molecular switch with UV/vis light as inputs and electrochemical signals as outputs was obtained.
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| 6. |
- 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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| 7. |
- Fu, Yao, et al.
(författare)
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Duet of Acetate and Water at the Defects of Metal-Organic Frameworks
- 2019
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Ingår i: Nano letters (Print). - : American Chemical Society (ACS). - 1530-6984 .- 1530-6992. ; 19:3, s. 1618-1624
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Tidskriftsartikel (refereegranskat)abstract
- Metal-organic frameworks (MOFs) are porous crystalline materials with promising applications in molecular adsorption, separation, and catalysis. It has been discovered recently that structural defects introduced unintentionally or by design could have a significant impact on their properties. However, the exact chemical composition and structural evolution under different conditions at the defects are still under debate. In this study, we performed multidimensional solid-state nuclear magnetic resonance (SSNMR) coupled with computer simulations to elucidate an important scenario of MOF defects, uncovering the dynamic interplay between residual acetate and water. Acetate, as a defect modulator, and water, as a byproduct, are prevalent defect-associated species, which are among the key factors determining the reactivity and stability of defects. We discovered that acetate molecules coordinate to a single metal site monodentately and pair with water at the neighboring position. The acetates are highly flexible, which undergo fast libration as well as a slow kinetic exchange with water through dynamic hydrogen bonds. The dynamic processes under variable temperatures and different hydration levels have been quantitatively analyzed across a broad time scale from microseconds to seconds. The integration of SSNMR and computer simulations allows a precision probe into defective MOF structures with intrinsic dynamics and disorder.
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| 8. |
- Gao, Li, et al.
(författare)
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A mechanistic hypothesis for the cytochrome P450-catalyzed cis-trans isomerization of 4-hydroxytamoxifen : an unusual redox reaction
- 2011
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Ingår i: Journal of Chemical Information and Modeling. - : American Chemical Society (ACS). - 1549-9596 .- 1549-960X. ; 51:9, s. 2293-2301
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Tidskriftsartikel (refereegranskat)abstract
- We provide a detailed description of the cis-trans isomerization of 4-hydroxytamoxifen/endoxifen catalyzed by several isoforms from the cytochrome P450 (CYP) superfamily, including CYP1B1, CYP2B6, and CYP2C19. We show that the reactions mainly involve redox processes catalyzed by CYP, DFT calculation results strongly suggest that the isomerization occurs via a cationic intermediate. The cationic cis-isomer is more than 3 kcal/mol more stable than the trans form, resulting in an easier conversion from trans-to-cis than cis-to-trans. The cis-trans isomerization is a rarely reported CYP reaction and is ascribed to the lack of a second abstractable proton on the ethenyl group of the triarylvinyl class of substrates. The cationic intermediates thus formed instead of the stable dehydrogenation products allow for isomerization to occur. As a comparison, the reactions for the tamoxifen derivatives are compared to those of other substrates, 4-hydroxyacetanilide and raloxifene, for which the stable dehydrogenation products are formed.
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| 9. |
- Gao, Li, et al.
(författare)
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Characterization of Agonist Binding to His524 in the Estrogen Receptor alpha Ligand Binding Domain
- 2012
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Ingår i: Journal of Physical Chemistry B. - : American Chemical Society (ACS). - 1520-6106 .- 1520-5207. ; 116:16, s. 4823-4830
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Tidskriftsartikel (refereegranskat)abstract
- The bioactivities of the natural steroidal estrogen 17 beta-estradiol (E-2), the synthetic estrogen diethylstilbestrol (DES), and the phytoestrogen genistein (GEN) are intimately associated with their binding to the estrogen receptor alpha ligand binding domain (ER alpha LBD) and accordingly allostery. Molecular modeling techniques have been performed on agonists in complex with the LBD, focusing on the pivotal role of His524 modeled as the epsilon-tautomer and the protonated form (depending on pH). It is found that E-2 binds to the active LBD with the aid of Leu525, showing existing stable patterns of an H-binding network with Glu419 via His524 in all models. The main difference seen in the effect is that the full agonists E-2 and DES have higher binding energies to the protonated His524 than the partial agonists GEN and Way-169916 (W), which is in line with noted experimental transcriptional activities. In conclusion, the study demonstrates that the phytoestrogen GEN interacts differently with the LBD than what E-2 and DES do, which explains the observed signaling differences.
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| 10. |
- Gao, Li, et al.
(författare)
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Conformational enantiomerization and estrogen receptor alpha binding of anti-cancer drug tamoxifen and its derivatives
- 2011
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Ingår i: Journal of Chemical Information and Modeling. - : American Chemical Society (ACS). - 1549-9596 .- 1549-960X. ; 51:2, s. 306-314
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Tidskriftsartikel (refereegranskat)abstract
- The anticancer drug tamoxifen (TAM) displays two chiral vinyl propeller structures, which interconvert so rapidly that the process is undetectable on the NMR time scale. In the present work, the enantiomerization processes were investigated with molecular modeling techniques. The threshold mechanisms probed at the different rings were shown to be identical, i.e., involving a synchronous three-ring flip, with a correlated rotation of the rings. In order to reveal the pharmacological profiles of the two chiral forms, we performed structural studies on the ligand binding domain of estrogen receptor alpha. (ER alpha LBD) and associated ligands. The enantiomers, with opposite torsional twist, were found to be discriminated by ER alpha. For TAM and its main metabolites, the effects of the stereoselectivity of ER alpha are overcome by the low energy cost for helical inversion between the two torsional enantiomers, estimated to be similar to 3 kcal/mol.
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| 11. |
- Gao, Li, et al.
(författare)
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Modification of the anticancer drug tamoxifen to avoid CYP2D6 polymorphism
- 2013
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Ingår i: Canadian Journal of Chemistry-Revue Canadienne De Chimie. - : Canadian Science Publishing. - 0008-4042 .- 1480-3291. ; 91:9, s. 916-924
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Tidskriftsartikel (refereegranskat)abstract
- The prodrug tamoxifen (TAM) is the most widely used drug to treat breast cancer, and is metabolised to the active 4-hydroxy derivatives dominantly by hepatic CYP2D6. However, the application to patients with different polymorphic CYP2D6 has been under debate, because the efficacy of TAM is suspected to be suppressed in patients who have diminished CYP2D6 activity, resulting in inadequate active metabolites. We here propose modified structures, such as 4-methylTAM, which is highly possible to be activated by CYP3A, the most abundant CYP isoforms in the liver, whereby the genetic polymorphism of CYP2D6 is avoided. The diversity of CYP catalyzed metabolic paths for TAM and its derivatives are studied by quantum chemistry calculations on the reaction energies of the initial H atom abstraction steps. The ability of forming DNA adducts is compared through the formation enthalpy of the carbocation intermediate. The results suggest that the modified structures are safe with regard to forming DNA adducts and may be used as prodrugs in a wide range of patients, due to CYP3A, rather than CYP2D6, mediated activation.
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| 12. |
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| 13. |
- Gao, Li, et al.
(författare)
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More stable, more estrogenic: the SERM-ERα LBD complex
- 2011
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Ingår i: Journal of Biophysical Chemistry. - : Scientific Research Publishing, Inc.. - 2153-036X .- 2153-0378. ; 2:3, s. 233-243
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Tidskriftsartikel (refereegranskat)abstract
- Many synthetic selective estrogen receptor mo- dulators (SERMs) have been cocrystallized with the human estrogen receptor α ligand binding domain (ERα LBD). Despite stabilizing the same canonical inactive conformation of the LBD, most SERMs display different ligand-dependent pharmacological profiles. We show here that in-creased partial agonism of SERMs is associated with increased conformational stability of the SERM-LBD complexes, by investigation of dihy-drobenzoxathiin-based SERMs using molecular modelling techniques. Analyses of tamoxifen (TAM) and 4-hydroxytamoxifen (OHT) in complex with the LBD furthermore indicates that the conversion of TAM to OHT increases both the affinity to ERα and the partial agonism of the anti-cancer drug, which provides a plausible ex-planation of the counterintuitive results of TAM therapy.
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| 14. |
- Guanglin, Kuang, 1987-
(författare)
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Theoretical Studies of Protein-Ligand Interactions
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The protein-ligand interaction is an important issue in rational drug design and protein function research. This thesis focuses on the study of protein-ligand interactions using various molecular modeling methods, which are used in combination to predict the binding modes and calculate the binding free energies of several important protein-ligand systems, as summarized below.In Paper I, we investigated the binding profile of a type I positive allosteric modulator (PAM) NS-1738 with the α7-nicotinic acetylcholine receptor (α7-nAChR). NS-1738 is found to have three different binding sites on α7-nAChR and has moderate binding affinities to the receptor.In Paper II, we revealed the binding mechanism of a PET radio-ligand [18F]ASEM with α7-nAChR. Using metadynamics simulations, we managed to find a stable state which is not observed in molecular docking and unbiased molecular dynamics simulations. Free energy analysis further confirmed that this stable state is the global minimum with respect to the selected collective variables.In Paper III, we studied the binding modes and binding affinities of two probes (AZD2184 and thioflavin T) for the detection of amyloid β(1-42) fibrils in clinical studies. We found that AZD2184 and thioflavin T are able to bind to several sites of the Aβ(1-42) fibril. Due to the small size, planarity and neutrality of AZD2184, it binds more strongly with Aβ(1-42) fibril at all sites. By contrast, thioflavin T has more significant conformational changes after binding, which is the reason that thioflavin T can be used as a fluorescent probe in in vitro studies.In Paper IV, we studied the binding profile of PtdIns(3,4,5)P3 with the plecsktrin homology (PH) domain of Saprolegnia monoica cellulose synthase. We first studied the binding modes of the inositol groups with the PH domain in solution, the results of which were then used to guide the modeling of the binding mode of PtdIns(3,4,5)P3 in a membrane with the PH domain.
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| 15. |
- Guanglin, Kuang, et al.
(författare)
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Theoretical study of the binding profile of an allosteric modulator NS-1738 with a chimera structure of the alpha 7 nicotinic acetylcholine receptor
- 2016
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Ingår i: Physical Chemistry, Chemical Physics - PCCP. - : Royal Society of Chemistry. - 1463-9076 .- 1463-9084. ; 18:40, s. 28003-28009
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Tidskriftsartikel (refereegranskat)abstract
- Potentiation of the function of the alpha 7 nicotinic acetylcholine receptor (alpha 7-nAChR) is believed to provide a possible way for the treatment of cholinergic system dysfunctions such as Alzheimer's disease and schizophrenia. Positive allosteric modulators (PAMs) are able to augment the peak current response of the endogenous agonist of alpha 7-nAChR by binding to some allosteric sites. In this study, the binding profile of a potent type I PAM, NS-1738, with a chimera structure (termed alpha 7-AChBP) constructed from the extracellular domain of alpha 7-nAChR and an acetylcholine binding protein was investigated with molecular docking, molecular dynamics simulation, and free energy calculation methods. We found that NS-1738 could bind to three allosteric sites of alpha 7-AChBP, namely, the top pocket, the vestibule pocket and the agonist sub-pocket. NS-1738 has moderate binding affinities (-6.76 to -9.15 kcal mol(-1)) at each allosteric site. The urea group is critical for binding and can form hydrogen-bond interactions with the protein. The bulky trifluoromethyl group also has a great impact on the binding modes and binding affinities. We believe that our study provides valuable insight into the binding profiles of type I PAMs with alpha 7-nAChR and is helpful for the development of novel PAMs.
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| 16. |
- He, Liming, et al.
(författare)
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A new relativistic Hartree-Fock calculation scheme and its application to the evaluation of fine-structure intervals for nd (n=3-40) series of sodium
- 2011
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Ingår i: Journal of Physics B. - : IOP Publishing. - 0953-4075 .- 1361-6455. ; 44:22, s. 225007-
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Tidskriftsartikel (refereegranskat)abstract
- We present a new second-order representation of the relativistic Hartree-Fock equation, which can be solved by the standard Hartree-Fock technique. An alternative reduction for the magnetic part of the Breit interaction is presented in an explicit expression. A corresponding program has been developed, which improves significantly the scaled linear mesh introduced by Herman and Skillman. The structures for a number of atoms and ions are calculated and the agreement of our results with those published is excellent. We evaluate the fine-structure intervals of nd(n = 3-40) Rydberg series for sodium. The inverted fine-structure splitting values are obtained directly as the differences of eigenvalues obtained from a self-consistent field procedure. Taking into account the Gaunt effect enables the accuracy of the calculation to be substantially improved. The complete treatments reproduce very well the inverted fine structures along the Rydberg series and the relative difference between the present results and the experiments does not exceed 4.4%.
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| 17. |
- Hede, Thomas, 1975-, et al.
(författare)
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A theoretical study revealing the promotion of light-absorbing carbon particles solubilization by natural surfactants in nanosized water droplets
- 2013
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Ingår i: Atmospheric Science Letters. - : Wiley. - 1530-261X. ; 14:2, s. 86-90
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Tidskriftsartikel (refereegranskat)abstract
- Many identified effects of atmospheric aerosol particles on climate come from pollutants. The effects of light-absorbing carbon particles (soot) are amongst the most uncertain and they are also considered to cause climate warming on the same order of magnitude as anthropogenic carbon dioxide. This study contributes to the understanding of the potential for transformation of the surface character of soot from hydrophobic to hydrophilic, which in clouds promotes a build-up of water-soluble material. We use molecular dynamics simulations to show how natural surfactants facilitate solubilization of fluoranthene, which we use as a model compound for soot in nanoaerosol water clusters.
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| 18. |
- Hede, Thomas, et al.
(författare)
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HULIS in Nanoaerosol Clusters; Investigations of Surface Tension and Aggregate Formation using Molecular Dynamics Simulations
- 2011
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Ingår i: Atmospheric Chemistry and Physics Discussions. - : Copernicus GmbH. - 1680-7367 .- 1680-7375.
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Cloud condensation nuclei act as cores for water vapor condensation, and their composition and chemical properties may enhance or depress the ability for droplet growth. In this study we use molecular dynamics simulations to show that humic-like substances of larger systems (8.6 nm in diameter) mimic experimental data well referring to reduction of surface tension. The structural properties examined show the ability for the humic-like substances to aggregate inside the nanoaerosol clusters.
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| 19. |
- Hede, Thomas, 1975-, et al.
(författare)
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Model HULIS compounds in nanoaerosol clusters : investigations of surface tension and aggregate formation using molecular dynamics simulations
- 2011
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Ingår i: Atmospheric Chemistry And Physics. - : Copernicus GmbH. - 1680-7316 .- 1680-7324. ; 11:13, s. 6549-6557
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Tidskriftsartikel (refereegranskat)abstract
- Cloud condensation nuclei act as cores for water vapour condensation, and their composition and chemical properties may enhance or depress the ability for droplet growth. In this study we use molecular dynamics simulations to show that model humic-like substances (HULIS) in systems containing 10 000 water molecules mimic experimental data well referring to reduction of surface tension. The model HULIS compounds investigated in this study are cis-pinonic acid (CPA), pinic acid (PAD) and pinonaldehyde (PAL). The structural properties examined show the ability for the model HULIS compounds to aggregate inside the nanoaerosol clusters.
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| 20. |
- Hussain, M., et al.
(författare)
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ATAD2 in cancer : a pharmacologically challenging but tractable target
- 2018
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Ingår i: Expert opinion on therapeutic targets. - : Taylor and Francis Ltd. - 1472-8222 .- 1744-7631. ; 22:1, s. 85-96
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: ATAD2 protein is an emerging oncogene that has strongly been linked to the etiology of multiple advanced human cancers. Therapeutically, despite the fact that genetic suppression/knockdown studies have validated it as a compelling drug target for future therapeutic development, recent druggability assessment data suggest that direct targeting of ATAD2’s bromodomain (BRD) may be a very challenging task. ATAD2’s BRD has been predicted as a ‘difficult to drug’ or ‘least druggable’ target due to the concern that its binding pocket, and the areas around it, seem to be unfeasible for ligand binding. Areas covered: In this review, after shedding light on the multifaceted roles of ATAD2 in normal physiology as well as in cancer-etiology, we discuss technical challenges rendered by ATAD2’s BRD active site and the recent drug discovery efforts to find small molecule inhibitors against it. Expert opinion: The identification of a novel low-nanomolar semi-permeable chemical probe against ATAD2’s BRD by recent drug discovery campaign has demonstrated it to be a pharmacologically tractable target. Nevertheless, the development of high quality bioavailable inhibitors against ATAD2 is still a pending task. Moreover, ATAD2 may also potentially be utilized as a promising target for future development of RNAi-based therapy to treat cancers.
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| 21. |
- Kang, Yu, et al.
(författare)
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Na+ and K+ ion selectivity by size-controlled biomimetic graphene nanopores
- 2014
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Ingår i: Nanoscale. - : Royal Society of Chemistry (RSC). - 2040-3364 .- 2040-3372. ; 6:18, s. 10666-10672
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Tidskriftsartikel (refereegranskat)abstract
- Because biological ionic channels play a key role in cellular transport phenomena, they have attracted extensive research interest for the design of biomimetic nanopores with high permeability and selectivity in a variety of technical applications. Inspired by the structure of K+ channel proteins, we designed a series of oxygen doped graphene nanopores of different sizes by molecular dynamics simulations to discriminate between K+ and Na+ channel transport. The results from free energy calculations indicate that the ion selectivity of such biomimetic graphene nanopores can be simply controlled by the size of the nanopore; compared to K+, the smaller radius of Na+ leads to a significantly higher free energy barrier in the nanopore of a certain size. Our results suggest that graphene nanopores with a distance of about 3.9 A between two neighboring oxygen atoms could constitute a promising candidate to obtain excellent ion selectivity for Na+ and K+ ions.
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| 22. |
- Kang, Yu, et al.
(författare)
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On the Mechanism of Protein Adsorption onto Hydroxylated and Nonhydroxylated TiO2 Surfaces
- 2010
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Ingår i: The Journal of Physical Chemistry C. - Washington DC, USA : American Chemical Society (ACS). - 1932-7447 .- 1932-7455. ; 114:34, s. 14496-14502
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Tidskriftsartikel (refereegranskat)abstract
- Protein adsorption onto implant surfaces is of great importance for the regulation of implant bioactivity. Surface modification of implants is a promising way in the molecular design of biocompatible materials against nonspecific adsorption of proteins. On the basis of these fundamental facts, we focus in this work on the different behavior of protein adsorption on hydroxylated and nonhydroxylated rutile TiO2 (110) surfaces through molecular dynamics simulations. Our investigation indicates that the distribution of the water molecules at the interface induced by the surface modification plays an important role in the protein adsorption. The surface with modified hydroxyl groups was observed to have much greater affinity to the protein, as reflected by the larger protein-surface electrostatic interaction and by the larger amount of adsorbed residues. The highly ordered structure of the modified hydroxyl groups on the hydroxylated surface diminishes the possibility of hydrogen bond formation between the surface and the water molecules above it, which in turn makes it easier for the protein to move closer to the surface with hydroxyl modification.
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| 23. |
- Kang, Zhengzhong, 1990-, et al.
(författare)
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Adsorption and folding of single strand DNA on metal-organic frameworks: a molecular simulation study
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- DNA-MOF nanoparticles based on the loading, release, and conformational change of DNA on MOFs have been frequently explored in gene therapy, drug delivery, and biosensor design. Nevertheless, the mechanism of DNA-MOF interactions, which is a fundamental issue behind these applications, remains largely unclear. Here, we applied molecular simulation methods to study systematically the adsorption and folding of ssDNA with different sequences on ideal and defective UiO-66-NH2 MOFs. We find that the ssDNA prefers to be adsorbed on the surfaces rather than inside the cages due to the size limitation of the cages. It is difficult for the ssDNA to be adsorbed on the ideal MOF surface through van der Waals interactions but it can be stably loaded on the defective MOF surface through electrostatic interactions. The whole process of the ssDNA adsorption onto the defective MOFs includes three stages: fast adsorption, conformational reconfiguration, and lock-down adsorption. The loading state of the ssDNA on UiO-66-NH2 is the coexistence of the adsorbed and dangling nucleotides. The binding of the ssDNA on the MOFs is dominated by the multiple point anchoring of the phosphate groups of the ssDNA on the clusters of UiO-66-NH2. Water layers with complex hydrogen-bond network function as a gate, preventing the ssDNA from approaching to UiO-66-NH2 before adsorption and inhibiting it from leaving UiO-66-NH2 after anchoring. Unlike the circular folding structure in the solution, the adsorbed ssDNA displays a slender conformation or duplex like structure. Our results thus provide a deep understanding of DNA-MOF interactions.
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| 24. |
- 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
-
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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| 25. |
- Kuang, Guanglin, et al.
(författare)
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Computational studies of the binding profile of phosphoinositide PtdIns (3,4,5) P-3 with the pleckstrin homology domain of an oomycete cellulose synthase
- 2016
-
Ingår i: Scientific Reports. - : Nature Publishing Group. - 2045-2322. ; 6
-
Tidskriftsartikel (refereegranskat)abstract
- Saprolegnia monoica is a model organism to investigate Saprolegnia parasitica, an important oomycete which causes considerable loss in aquaculture every year. S. monoica contains cellulose synthases vital for oomycete growth. However, the molecular mechanism of the cellulose biosynthesis process in the oomycete growth is still poorly understood. Some cellulose synthases of S. monoica, such as SmCesA2, are found to contain a plecsktrin homology (PH) domain, which is a protein module widely found in nature and known to bind to phosphoinositides, a class of signaling compounds involved in many biological processes. Understanding the molecular interactions between the PH domain and phosphoinositides would help to unravel the cellulose biosynthesis process of oomycetes. In this work, the binding profile of PtdIns (3,4,5) P-3, a typical phosphoinositide, with SmCesA2-PH was studied by molecular docking, molecular dynamics and metadynamics simulations. PtdIns (3,4,5) P-3 is found to bind at a specific site located at beta 1, beta 2 and beta 1-beta 2 loop of SmCesA2-PH. The high affinity of PtdIns (3,4,5) P-3 to SmCesA2-PH is contributed by the free phosphate groups, which have electrostatic and hydrogenbond interactions with Lys88, Lys100 and Arg102 in the binding site.
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| 26. |
- Kuang, Guanglin, et al.
(författare)
-
Insight into the adsorption profiles of the Saprolegnia monoica chitin synthase MIT domain on POPA and POPC membranes by molecular dynamics simulation studies
- 2016
-
Ingår i: Physical Chemistry, Chemical Physics - PCCP. - : Royal Society of Chemistry. - 1463-9076 .- 1463-9084. ; 18:7, s. 5281-5290
-
Tidskriftsartikel (refereegranskat)abstract
- The critical role of chitin synthases in oomycete hyphal tip growth has been established. A microtubule interacting and trafficking (MIT) domain was discovered in the chitin synthases of the oomycete model organism, Saprolegnia monoica. MIT domains have been identified in diverse proteins and may play a role in intracellular trafficking. The structure of the Saprolegnia monoica chitin synthase 1 (SmChs1) MIT domain has been recently determined by our group. However, although our in vitro assay identified increased strength in interactions between the MIT domain and phosphatidic acid (PA) relative to other phospholipids including phosphatidylcholine (PC), the mechanism used by the MIT domain remains unknown. In this work, the adsorption behavior of the SmChs1 MIT domain on POPA and POPC membranes was systematically investigated by molecular dynamics simulations. Our results indicate that the MIT domain can adsorb onto the tested membranes in varying orientations. Interestingly, due to the specific interactions between MIT residues and lipid molecules, the binding affinity to the POPA membrane is much higher than that to the POPC membrane. A binding hotspot, which is critical for the adsorption of the MIT domain onto the POPA membrane, was also identified. The lower binding affinity to the POPC membrane can be attributed to the self-saturated membrane surface, which is unfavorable for hydrogen-bond and electrostatic interactions. The present study provides insight into the adsorption profile of SmChs1 and additionally has the potential to improve our understanding of other proteins containing MIT domains.
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| 27. |
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| 28. |
- Kuang, Guanglin, et al.
(författare)
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Investigation of the Binding Profiles of AZD2184 and Thioflavin T with Amyloid-beta(1-42) Fibril by Molecular Docking and Molecular Dynamics Methods
- 2015
-
Ingår i: Journal of Physical Chemistry B. - : American Chemical Society (ACS). - 1520-6106 .- 1520-5207. ; 119:35, s. 11560-11567
-
Tidskriftsartikel (refereegranskat)abstract
- Detecting deposits of amyloid beta fibrils in the brain is of paramount importance for an early diagnosis of Alzheimer's disease. A number of PET tracers have been developed for amyloid imaging, but many suffer from poor specificity and large signal to background ratio. Design of tracers with specificity and improved binding affinity requires knowledge about various potential binding sites in the amyloid beta fibril available for the tracers and the nature of the local microenvironment of these sites. In this study we investigate the local structure of fibrils using two important probes, namely, thioflavin T (a fluorescent probe) and AZD2184 (a PET tracer). The target structures for amyloid-beta(1-42) fibril are based on reported NMR solution models. By explicitly considering the effect of fibril flexibility on the available binding sites for all these models, the binding affinity of these probes has been investigated. The binding profiles of AZD2184 and thioflavin T were studied by molecular docking and molecular dynamics simulation methods. The two compounds were found to bind at the same sites of the fibril: three of which are within the fibril, and one is on the two sides of the Met35 residue on the surface. The binding affinity of AZD2184 and thioflavin T is found to be higher at the core sites than on the surface due to more contact residues. The binding affinity of AZD2184 is much higher than that of thioflavin T at every site due to electrostatic interaction and spatial restriction, which is in good agreement with experimental observation. However, the structural change of thioflavin T is much more significant than that of AZD2184, which is the chemical basis for its usage as a fluorescent probe. The ramifications of these results for the design and optimization of PET radioligands and fluorescent probes are briefly discussed.
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| 29. |
- Li, Gao
(författare)
-
Theoretical Studies of Anti-cancer Drug Tamoxifen and Estrogen Receptor Alpha
- 2012
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- For decades tamoxifen (TAM) has been widely used for treatment of breast cancer by mediating mainly the estrogen receptor α (ERα) signaling pathways, whereby it suppresses estrogen stimulated cancer cell growth. The clinical response of TAM has been linked to cytochrome P450 2D6 (CYP2D6), which is the main isoform responsible for the conversion of TAM to the active metabolites 4-hydroxyTAM (OHT) and endoxifen. Numerous clinical studies have thus attempted to assess the effects of CYP2D6 genetic variants on patients treated by TAM. However, the studies have resulted in contradictive conclusions. This thesis focuses on computational investigations of TAM and its main target ERα. The results obtained describe how the ligands contact with the ERα ligand binding domain (LBD), and provide possible mechanisms responsible for the CYP2D6 activating in TAM treatment. In addition, the CYP-mediated biotransformation of TAM-like compounds is investigated. All studies in this thesis aim to a step towards developing improved therapeutic agents for breast cancer treatment. In paper I, molecular dynamics simulations of ligand-LBD complexes have been performed. The results indicate that although OHT is a high affinity metabolite, it may have more undesired estrogen-like properties than the parent drug TAM, as a consequence of the additional 4-hydroxy group. In papers II and V, quantum mechanics calculations have been performed to study how the ligands are bound to ERα LBD. It is found that different conformational isomers of TAM-like ligands are discriminated by the LBD. The interactions between ligands and His524-Leu525 in the LBD are correlated with the transcriptional activity of estrogen agonist compounds. In papers III and IV, different CYP-mediated biotransformations of TAM and derivatives are studied. Based on the results from the computations, we suggest two modified compounds which are highly possible to be activated by other CYP isoforms besides CYP2D6, thereby avoiding CYP2D6 genetic polymorphism. Overall, the results generally agree with the hitherto available experimental results. Further experimental studies are needed to verify the proposed principles of ligands signaling through ERα, and to test the suggested CYP-mediated reactions and the bioactivity of the modified compounds.
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| 30. |
- Li, Jiachen, et al.
(författare)
-
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-
-
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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| 31. |
- Li, Jiachen, et al.
(författare)
-
Binding modes of prothrombin cleavage site sequences to the factor Xa catalytic triad : Insights from atomistic simulations
- 2022
-
Ingår i: Computational and Structural Biotechnology Journal. - : Elsevier BV. - 2001-0370. ; 20, s. 5401-5408
-
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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| 32. |
- Li, Junhao, et al.
(författare)
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Computational Insight Into Vitamin K-1 omega-Hydroxylation by Cytochrome P450 4F2
- 2018
-
Ingår i: Frontiers in Pharmacology. - : Frontiers Media S.A.. - 1663-9812. ; 9
-
Tidskriftsartikel (refereegranskat)abstract
- Vitamin K-1 (VK1) plays an important role in the modulation of bleeding disorders. It has been reported that omega-hydroxylation on the VK1 aliphatic chain is catalyzed by cytochrome P450 4F2 (CYP4F2), an enzyme responsible for the metabolism of eicosanoids. However, the mechanism of VK1 omega-hydroxylation by CYP4F2 has not been disclosed. In this study, we employed a combination of quantum mechanism (QM) calculations, homology modeling, molecular docking, molecular dynamics (MD) simulations, and combined quantum mechanism/molecular mechanism (QM/MM) calculations to investigate the metabolism profile of VK1 omega-hydroxylation. QM calculations based on the truncated VK1 model show that the energy barrier for omega-hydroxylation is about 6-25 kJ/mol higher than those at other potential sites of metabolism. However, results from the MD simulations indicate that hydroxylation at the omega-site is more favorable than at the other potential sites, which is in accordance with the experimental observation. The evaluation of MD simulations was further endorsed by the QM/MM calculation results. Our studies thus suggest that the active site residues of CYP4F2 play a determinant role in the omega-hydroxylation. Our results provide structural insights into the mechanism of VK1 omega-hydroxylation by CYP4F2 at the atomistic level and are helpful not only for characterizing the CYP4F2 functions but also for looking into the omega-hydroxylation mediated by other CYP4 enzymes.
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| 33. |
- Li, Junhao, 1989-, et al.
(författare)
-
Dissecting the Structural Plasticity and Dynamics of Cytochrome P450 2B4 by Molecular Dynamics Simulations
-
Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- The plasticity of cytochrome P450 enzymes (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 that 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 structures. The subsequent 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 intermediate. Our results thus unveil the mechanism of dimer formation and open-to-intermediate transition for CYP2B4 in the water and membrane environments.
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| 34. |
- Li, Junhao, et al.
(författare)
-
Dissecting the Structural Plasticity and Dynamics of Cytochrome P450 2B4 by Molecular Dynamics Simulations
- 2020
-
Ingår i: Journal of Chemical Information and Modeling. - : American Chemical Society (ACS). - 1549-9596 .- 1549-960X. ; 60:10, s. 5026-5035
-
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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| 35. |
- Li, Junhao, et al.
(författare)
-
Homotropic Cooperativity of Midazolam Metabolism by Cytochrome P450 3A4 : Insight from Computational Studies
- 2021
-
Ingår i: Journal of Chemical Information and Modeling. - : American Chemical Society (ACS). - 1549-9596 .- 1549-960X. ; 61:5, s. 2418-2426
-
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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| 36. |
- Li, Junhao, 1989-, et al.
(författare)
-
Mechanism of the Homotropic Cooperativity of Midazolam Metabolism by Cytochrome P450 3A4: Insight from Computational Studies
-
Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Midazolam (MDZ) is a commonly used drug and is metabolized by cytochrome P450 3A4 (CYP3A4). It has been reported that the ratio of the hydroxylation products, 1'-OH-MDZ/4-OH-MDZ, is dependent on the MDZ concentration, which reflects that there exists the homotropic cooperative behavior in the CYP3A4-mediated hydroxylation of MDZ. Here, we used quantum chemistry (QC), molecular docking, conventional molecular dynamics (cMD) simulation, and Gaussian accelerated molecular dynamics (GaMD) simulation approaches to investigate the mechanism of the interactions between CYP3A4 and MDZ. Our study suggests that the H41 site, i.e. the pro-R center, is the most reactive site for the hydrogen abstraction, followed by the C1' site. However, the product 4-OH-MDZ is likely to be racemic due to the chirality inversion in the rebound step. We found that the allosteric site was not involved in the ligand cooperativity and the observation that there exists one or two MDZs in the productive site is in line with the experimental observations.
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| 37. |
- Li, Junhao, 1989-, et al.
(författare)
-
Mechanistic Insights into the Regio‐ and Stereoselectivities of Testosterone and Dihydrotestosterone Hydroxylation Catalyzed by CYP3A4 and CYP19A1
- 2020
-
Ingår i: Chemistry - A European Journal. - Weinheim, Germany : Wiley. - 0947-6539 .- 1521-3765. ; 26:28, s. 6214-6223
-
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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| 38. |
- Li, Junhao, 1989-
(författare)
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Theoretical Studies of Drug-Metabolizing Cytochrome P450 Enzymes
- 2020
-
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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| 39. |
- Li, S., et al.
(författare)
-
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
-
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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| 40. |
- Li, Xin, et al.
(författare)
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Cloud droplet activation mechanisms of amino acid aerosol particles : insight from molecular dynamics simulations
- 2013
-
Ingår i: Tellus. Series B, Chemical and physical meteorology. - : Stockholm University Press. - 0280-6509 .- 1600-0889. ; 65, s. 65-
-
Tidskriftsartikel (refereegranskat)abstract
- Atmospheric amino acids constitute a large fraction of water-soluble organic nitrogen compounds in aerosol particles, and have been confirmed as effective cloud condensation nuclei (CCN) materials in laboratory experiments. We present a molecular dynamics (MD) study of six amino acids with different structures and chemical properties that are relevant to the remote marine atmospheric aerosol-cloud system, with the aim of investigating the detailed mechanism of their induced changes in surface activity and surface tension, which are important properties for cloud drop activation. Distributions and orientations of the amino acid molecules are studied; these L-amino acids are serine (SER), glycine (GLY), alanine (ALA), valine (VAL), methionine (MET) and phenylalanine (PHE) and are categorised as hydrophilic and amphiphilic according to their affinities to water. The results suggest that the presence of surface-concentrated amphiphilic amino acid molecules give rise to enhanced Lennard-Jones repulsion, which in turn results in decreased surface tension of a planar interface and an increased surface tension of the spherical interface of droplets with diameters below 10 nm. The observed surface tension perturbation for the different amino acids under study not only serves as benchmark for future studies of more complex systems, but also shows that amphiphilic amino acids are surface active. The MD simulations used in this study reproduce experimental results of surface tension measurements for planar interfaces and the method is therefore applicable for spherical interfaces of nano-size for which experimental measurements are not possible to conduct.
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| 41. |
- Li, Xin, et al.
(författare)
-
Cloud droplet activation mechanisms of amino acid aerosol particles : insight from molecular dynamics simulations
-
Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Atmospheric amino acids constitute a large fraction of water-soluble organic nitrogen compounds in aerosol particles, and have been confirmed as effective cloud condensation nuclei materials in laboratory experiments. We here present a molecular dynamics study of six amino acids with different structures and chemical properties that are relevant to the remote marine atmospheric aerosol-cloud system, with the aim to investigate the detailed mechanism of their induced changes in surface activity and surface tension, which are important properties for cloud drop activation. Distributions and orientations of the amino acid molecules are studied; these L-amino acids are serine, glycine, alanine, valine, methionine and phenylalanine and are categorized as hydrophilic and hydrophobic according to their affinities to water. The results suggest that the presence of surface-concentrated hydrophobic amino acid molecules give rise to enhanced Lennard-Jones repulsion, which in turn results in decreased surface tension of a planar interface but an increased surface tension of the spherical interface of droplets with diameters below 10 nm. The observed surface tension perturbation for the different amino acids under study not only serves as benchmark for future studies of more complex systems, but also shows that hydrophobic amino acids are surface active. The molecular dynamics simulations used in this study reproduce experimental results of surface tension measurements for planar interfaces and the method is therefore applicable for spherical interfaces of nano-size for which experimental measurements are not possible to conduct.
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| 42. |
- Li, Xin, et al.
(författare)
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Computer simulations of aqua metal ions for accurate reproduction of hydration free energies and structures
- 2010
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Ingår i: Journal of Chemical Physics. - Melville, USA : AIP Publishing. - 0021-9606 .- 1089-7690. ; 132:10, s. 104505-
-
Tidskriftsartikel (refereegranskat)abstract
- Metal ions play essential roles in biological processes and have attracted much attention in both experimental and theoretical fields. By using the molecular dynamics simulation technology, we here present a fitting-refining procedure for deriving Lennard-Jones parameters of aqua metal ions toward the ultimate goal of accurately reproducing the experimentally observed hydration free energies and structures. The polarizable SWM4-DP water model {proposed by Lamoureux [J. Chem. Phys. 119, 5185 (2003)]} is used to properly describe the polarization effects of water molecules that interact with the ions. The Lennard-Jones parameters of the metal ions are first obtained by fitting the quantum mechanical potential energies of the hexahydrated complex and are subsequently refined through comparison between the calculated and experimentally measured hydration free energies and structures. In general, the derived Lennard-Jones parameters for the metal ions are found to reproduce hydration free energies accurately and to predict hydration structures that are in good agreement with experimental observations. Dynamical properties are also well reproduced by the derived Lennard-Jones parameters.
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| 43. |
- Li, Xin, et al.
(författare)
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Cross-Linked Polysaccharide Assemblies in Marine Gels : An Atomistic Simulation
- 2013
-
Ingår i: The Journal of Physical Chemistry Letters. - : American Chemical Society (ACS). - 1948-7185. ; 4:16, s. 2637-2642
-
Tidskriftsartikel (refereegranskat)abstract
- Marine polymeric gels or colloidal nano- and microgels have been shown to contribute significantly to the primary marine aerosol and cloud condensation nuclei over remote marine areas. A microscopic understanding of such biologically derived matter at the sea air interface is important for future development of global climate models, but unfortunately cannot be obtained from modern characterization techniques. In this contribution, we employ molecular dynamics simulations to reveal the atomistic details of marine polymeric gels represented by anionic polysaccharide assemblies. The ionic bonds formed between polysaccharides and metal ions in seawater as well as the hydrophobic contribution to surface area are investigated in detail, and destabilization of the assemblies upon removal of Ca2+ or acidification is explained. These results provide insight into physicochemical properties of polysaccharide-Ca2+ structures and enable future studies of their roles of in the wetting process of cloud droplet activation.
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| 44. |
- Li, Xin, et al.
(författare)
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Glycine in aerosol water droplets : a critical assessment of Köhler theory by predicting surface tension from molecular dynamics simulations
- 2011
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Ingår i: Atmospheric Chemistry And Physics. - : Copernicus GmbH. - 1680-7316 .- 1680-7324. ; 11:2, s. 519-527
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Tidskriftsartikel (refereegranskat)abstract
- Aerosol particles in the atmosphere are important participants in the formation of cloud droplets and have significant impact on cloud albedo and global climate. According to the Kohler theory which describes the nucleation and the equilibrium growth of cloud droplets, the surface tension of an aerosol droplet is one of the most important factors that determine the critical supersaturation of droplet activation. In this paper, with specific interest to remote marine aerosol, we predict the surface tension of aerosol droplets by performing molecular dynamics simulations on two model systems, the pure water droplets and glycine in water droplets. The curvature dependence of the surface tension is interpolated by a quadratic polynomial over the nano-sized droplets and the limiting case of a planar interface, so that the so-called Aitken mode particles which are critical for droplet formation could be covered and the Kohler equation could be improved by incorporating surface tension corrections.
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| 45. |
- Li, Xin, et al.
(författare)
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Modulation of iridium(III) phosphorescence via photochromic ligands : a density functional theory study
- 2010
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Ingår i: Physical Chemistry, Chemical Physics - PCCP. - Stockholm, Sweden : Royal Society of Chemistry (RSC). - 1463-9076 .- 1463-9084. ; 12:41, s. 13730-13736
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Tidskriftsartikel (refereegranskat)abstract
- The photochromic iridium(III) complex (Py-BTE)(2)Ir(acac) synthesized by Tan et al. [W. Tan et al., Org. Lett. 2009, 11, 161-164] has shown distinct photo-reactivity and photo-controllable phosphorescence. We here present a density functional theory study on the (Py-BTE)(2)Ir(acac) complex to explore the mechanism at the molecular level and to help further design of photochromic iridium(III) complexes with the desirable properties. The hybrid functional PBE0, with 25% Hartree-Fock exchange, is found to give an optimal structure compared with X-ray crystallographic data. The absorption bands are well reproduced by using time-dependent density functional theory calculations, lending the possibility to assign the metal-to-ligand and intra-ligand charge transfer transitions. The radiative and nonradiative deactivation rate constants, k(r) and k(nr), are rationalized for both the open-ring and closed-ring forms of the complex. The very large k(nr) and small k(r) make the closed-ring form of the complex non-emissive. The triplet reactivity of the Py-BTE ligand is also studied by performing density functional theory calculations on the potential energy surfaces of the ground state and the lowest triplet state.
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| 46. |
- Li, Xin, et al.
(författare)
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Molecular Dynamics Study on the Surface Tension of Atmospheric Water Droplets Containing Amino Acids
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Atmospheric amino acids constitute an important fraction of the water-soluble organic nitrogen compounds in both marine and continental aerosols, and have been confirmed as effective cloud condensation nuclei materials in laboratory tests. We here present molecular dynamics study of six types of amino acids in atmospheric water droplets, in order to investigate molecular distributions, orientations and induced changes in surface tension, and to evaluate their indirect effects on optical properties of clouds. These amino acids, including serine, glycine, alanine, valine, methionine and phenylalanine, are categorized into hydrophilic and hydrophobic species according to their affinities to water. Different amino acids show distinct effects on the surface tension; even the same amino acid has different influence on the surface tension of planar and spherical interfaces. Finally the curvature dependence of the surface tension is modeled by a quadratic polynomial function of the inverse of droplet radius, and such relationship is used to improve the Köhler equation in predicting the critical supersaturation of droplet activation.
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| 47. |
- Li, Xin, et al.
(författare)
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Nuclear magnetic shielding of the Cd-113(II) ion in aqua solution : A combined molecular dynamics/density functional theory study
- 2008
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Ingår i: Journal of Physical Chemistry B. - : American Chemical Society (ACS). - 1520-6106 .- 1520-5207. ; 112:36, s. 11347-11352
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Tidskriftsartikel (refereegranskat)abstract
- We present a combined molecular dynamics simulation and density functional theory investigation of the nuclear magnetic shielding constant of the Cd-113(II) ion solvated in aqueous solution. Molecular dynamics simulations are carried out for the cadmium-water system in order to produce instantaneous geometries for subsequent determination of the nuclear magnetic shielding constant at the density functional theory level. The nuclear magnetic shielding constant is computed using a perturbation theory formalism, which includes nonrelativistic and leading order relativistic contributions to the nuclear magnetic Shielding tensor. Although the NMR shielding constant varies significantly with respect to simulation time, the value averaged over increasing number of snapshots remains almost constant. The paramagnetic nonrelativistic contribution is found to be most sensitive to dynamical changes in the system and is mainly responsible for the thermal and solvent effects in solution. The relativistic correction features very little sensitivity to the chemical environment, and can be disregarded in theoretical calculations when a Cd complex is used as reference compound in Cd-113 NMR experiments, due to the mutual cancelation between individual relativistic corrections.
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| 48. |
- Li, Xin, et al.
(författare)
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Paramagnetic Perturbation of the F-19 NMR Chemical Shift in Fluorinated Cysteine by O-2 : A Theoretical Study
- 2009
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Ingår i: Journal of Physical Chemistry B. - Washington, D. C. : American Chemical Society (ACS). - 1520-6106 .- 1520-5207. ; 113:31, s. 10916-10922
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Tidskriftsartikel (refereegranskat)abstract
- We present a combined molecular dynamics and density functional theory study of dioxygen-induced perturbation of the F-19 NMR chemical shifts in an aqueous solution of fluorinated cysteine under 100 atm of O-2 partial pressure. Molecular dynamics Simulations are carried out to determine the dominant structures of O-2 and the fluorinated cysteine complexes in water, and the collected structural information is exploited in computation of F-19 chemical shifts using density functional theory. The obtained results indicate that the density redistribution of the O-2 unpaired electrons between the dioxygen and fluorinated cysteine is responsible for the experimentally observed perturbation of the F-19 NMR chemical shifts, where the Fermi contact interaction plays the key role. The O-2-induced paramagnetic F-19 chemical shift, averaged over the simulation trajectory, is comparable with the reported experimental values, proving the availability of the developed strategy for modeling F-19 NMR chemical shifts in the presence of paramagnetic agents in ail aqueous solution. The applicability of the combined molecular dynamics/density functional theory approach for dioxygen NMR perturbation to all resonating nuclei including H-1, C-13, N-15, and F-19 is emphasized, and the ramification of this for investigations of membrane protein structures is discussed.
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| 49. |
- Li, Xin, et al.
(författare)
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Surface-Active cis-Pinonic Acid in Atmospheric Droplets : A Molecular Dynamics Study
- 2010
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Ingår i: The Journal of Physical Chemistry Letters. - Washington, USA : American Chemical Society (ACS). - 1948-7185. ; 1:4, s. 769-773
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Tidskriftsartikel (refereegranskat)abstract
- Water vapor in the atmosphere can condensate and form cloud droplets when there is a certain amount of humidity and a presence of cloud condensation nuclei, and organic solutes called surfactants can significantly lower the surface tension of water-one of the parameters determining cloud droplet population. We here present a molecular dynamics study of the behavior of cis-pinonic acid, a commonly found organic compound in cloud condensation nuclei, and its effect on the surface tension of water clusters. Specifically, the decrease in surface tension is found to depend on not only the concentration of the organic compound but also the droplet size due to the spontaneous assembly of the surfactant molecules on the droplet surface. This leads to the conclusion that the partitioning of the surfactant between the bulk and surface plays an important role in the behavior of atmospheric aerosol particles and thus in their availability for cloud formation.
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| 50. |
- Liang, Lijun, 1987-
(författare)
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Computational studies of DNA sequencing with graphene nanopores
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The aim of DNA sequencing is to obtain the order of DNA composition comprising the base pairs A (adenine) T (thymine), and C (cytosine) G (guanine). The fast development of DNA sequencing technology allows us to better understand the relationships among diseases, inheritance, and individuality. Solid state nanopores have been recommended as the next generation platform for DNA sequencing due to its low-cost and high-throughput. In particular, nanopores fabricated from graphene sheets are extremely thin and structurally robust and have been extensively used in DNA detection in recent years. In DNA sequencing, the translocation of a DNA molecule through a nanopore is known to be a very complicated issue and is affected by many factors, such as ion concentration, thickness of the nanopore, and the nanopore diameter. The technique of molecular dynamic simulations has been a complementary tool to study DNA translocation through nanopores. In this thesis, I summarize my work of computational studies of DNA sequencing using graphene nanopores. These studies include: DNA translocation through single-layer graphene nanopores of different diameters under conditions of various ion concentrations and applied voltages; DNA translocation through multilayer graphene nanopores varied from a single to a few layers; pulling out single strand DNA molecules from small graphene nanopores of different geometries. The major contributions of this work include:1. Effects of bias voltage on DNA translocation time were investigated leading to the insight that lower applied voltages can extend the time of DNA translocation through monolayer graphene nanopores. The effect of salt concentration on the corresponding ionic current was studied. At a low ionic concentration (< 0.3M), the current increases as DNA translocates through a nanopore. However, at a high ionic concentration (>0.5M), the current decreases as DNA translocates through the nanopore. A theoretical model was proposed to explore the relationship between the current and the occupied nanopore area. We demonstrated that the DNA translocation time can be prolonged by narrowing the diameter of a nanopore properly and the reduction of the blockade current depends on the ratio of the unoccupied nanopore area to the total nanopore area.2. DNA translocation through multilayer graphene nanopores was studied by molecular dynamics simulations with the aim to achieve single-base resolution. We show that the DNA translocation time can be extended by increasing the graphene layers up to a moderate number (7) and that the current in DNA translocation undergoes a stepwise change upon DNA going through an multi-layer graphene (MLG) nanopore. A model was built to account for the relationship between the current change and the unoccupied volume of the MLG nanopore. We demonstrate that the blockade current is closely related to the unoccupied volume. The dynamics of DNA translocation depends specifically on the interaction of nucleotides with the graphene sheet. Thus, our study indicates that the resolution of DNA detection can be improved by increasing the number of graphene layers in a certain range and by modifying the surface of graphene nanopores.3. The effect of graphene nanopore geometry on DNA sequencing has been assessed by steered molecular dynamics simulations. DNA fragments including A, T, C, G and 5-methylcytosine (MC) were pulled through graphene nanopores of different geometries with diameters down to ~1nm by steered molecular dynamics simulations. We demonstrated that the bases (A, T, C, G, and MC) can be indentified in single-base resolution by the characteristic force peak values in a circular graphene nanopore but not in graphene nanopores of other geometries. Symmetric nanopores are thus better suited to DNA sequence detection via force curves than asymmetric nanopores. This implies that the graphene nanopore surface should be modified as symmetric as possible to sequence DNA by an atomic force microscope or optical tweezers. This helps us to understand low-cost and time-efficient DNA sequencing in narrow nanopores.4. The translocation time for different nucleotides to pass through graphene nanopores with certain diameters was investigated. It was found that the translocation times are different for different bases under a low electric field. The results indicate that DNA can be sequenced by the translocation time to pass through a graphene nanopore.5. Inspired by the structure of K+ channel proteins, a series of oxygen doped graphene nanopores of different size were designed to discriminate the transport of K+ and Na+ ions. The results indicate that the ion selectivity of such biomimetic graphene nanopores can be simply controlled by the size of the nanopore. Compared to K+, the smaller radius of Na+ leads to a much higher free energy barrier in the nanopore of a certain size.
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