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  • 1. Brown, Christian
    et al.
    Szpryngiel, Scarlett
    Guanglin, Kuang
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Srivastava, Vaibhav
    Ye, Weihua
    McKee, Lauren S.
    Tu, Yaoquan
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Maler, Lena
    Bulone, Vincent
    Structural and functional characterization of the microtubule interacting and trafficking domains of two oomycete chitin synthases2016In: The FEBS Journal, ISSN 1742-464X, E-ISSN 1742-4658, Vol. 283, no 16, p. 3072-3088Article in journal (Refereed)
    Abstract [en]

    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 modeling. Our results suggest a potential function for these MIT domains in the intracellular transport and/or regulation of Chs enzymes in the oomycetes. DatabaseStructural data are available in the Biological Magnetic Resonance Bank (BMRB) database under the accession number 19987 and the PDB database under the accession number .

  • 2. Cheng, J.
    et al.
    Sun, Xianqiang
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Li, W.
    Liu, G.
    Tu, Yaoquan
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Tang, Y.
    Molecular switches of the κ opioid receptor triggered by 6′-GNTI and 5′-GNTI2016In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, article id 18913Article in journal (Refereed)
    Abstract [en]

    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.

  • 3.
    Gao, Li
    et al.
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Sun, Xianqiang
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Tu, Yaoquan
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Ågren, Hans
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Eriksson, Leif A.
    Modification of the anticancer drug tamoxifen to avoid CYP2D6 polymorphism2013In: Canadian journal of chemistry (Print), ISSN 0008-4042, E-ISSN 1480-3291, Vol. 91, no 9, p. 916-924Article in journal (Refereed)
    Abstract [en]

    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.

  • 4.
    Gao, Li
    et al.
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Tu, Yaoquan
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Eriksson, Leif A.
    More stable, more estrogenic: the SERM-ERα LBD complex2011In: Journal of Biophysical Chemistry, ISSN 2153-036X, E-ISSN 2153-0378, Vol. 2, no 3, p. 233-243Article in journal (Refereed)
    Abstract [en]

    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.

  • 5.
    Gao, Li
    et al.
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Tu, Yaoquan
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Ågren, Hans
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Eriksson, Leif A.
    Characterization of Agonist Binding to His524 in the Estrogen Receptor alpha Ligand Binding Domain2012In: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 116, no 16, p. 4823-4830Article in journal (Refereed)
    Abstract [en]

    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.

  • 6.
    Gao, Li
    et al.
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Tu, Yaoquan
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Ågren, Hans
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Eriksson, Leif A.
    Modification of the anticancerdrug tamoxifen to avoid CYP2D6 polymorphismManuscript (preprint) (Other academic)
  • 7.
    Guanglin, Kuang
    et al.
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Wang, Xu
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Halldin, Christer
    Nordberg, Agneta
    Långström, Bengt
    Ågren, Hans
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Tu, Yaoquan
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Theoretical study of the binding profile of an allosteric modulator NS-1738 with a chimera structure of the alpha 7 nicotinic acetylcholine receptor2016In: Physical Chemistry, Chemical Physics - PCCP, ISSN 1463-9076, E-ISSN 1463-9084, Vol. 18, no 40, p. 28003-28009Article in journal (Refereed)
    Abstract [en]

    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.

  • 8.
    He, Liming
    et al.
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Zhu, Yunxia
    Zhang, Meng
    Tu, Yaoquan
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    A new relativistic Hartree-Fock calculation scheme and its application to the evaluation of fine-structure intervals for nd (n=3-40) series of sodium2011In: Journal of Physics B: Atomic, Molecular and Optical Physics, ISSN 0953-4075, E-ISSN 1361-6455, Vol. 44, no 22, p. 225007-Article in journal (Refereed)
    Abstract [en]

    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%.

  • 9. Hede, T.
    et al.
    Li, Xin
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Leck, C.
    Tu, Yaoquan
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Ågren, Hans
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Model HULIS compounds in nanoaerosol clusters: investigations of surface tension and aggregate formation using molecular dynamics simulations2011In: Atmospheric Chemistry And Physics, ISSN 1680-7316, E-ISSN 1680-7324, Vol. 11, no 13, p. 6549-6557Article in journal (Refereed)
    Abstract [en]

    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.

  • 10. Hede, Thomas
    et al.
    Leck, Caroline
    Sun, Lu
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Tu, Yaoquan
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Ågren, Hans
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    A theoretical study revealing the promotion of light-absorbing carbon particles solubilization by natural surfactants in nanosized water droplets2013In: Atmospheric Science Letters, ISSN 1530-261X, E-ISSN 1530-261X, Vol. 14, no 2, p. 86-90Article in journal (Refereed)
    Abstract [en]

    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.

  • 11. Kang, Yu
    et al.
    Zhang, Zhisen
    Shi, Hui
    Zhang, Junqiao
    Liang, Lijun
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology. Zhejiang University, China .
    Wang, Qi
    Ågren, Hans
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Tu, Yaoquan
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Na+ and K+ ion selectivity by size-controlled biomimetic graphene nanopores2014In: Nanoscale, ISSN 2040-3364, E-ISSN 2040-3372, Vol. 6, no 18, p. 10666-10672Article in journal (Refereed)
    Abstract [en]

    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.

  • 12.
    Kuang, Guanglin
    et al.
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Bulone, Vincent
    KTH, School of Biotechnology (BIO), Glycoscience.
    Tu, Yaoquan
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Computational studies of the binding profile of phosphoinositide PtdIns (3,4,5) P-3 with the pleckstrin homology domain of an oomycete cellulose synthase2016In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, article id 20555Article in journal (Refereed)
    Abstract [en]

    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.

  • 13.
    Kuang, Guanglin
    et al.
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Liang, Lijun
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology. Zhejiang University, China.
    Brown, Christian
    KTH, School of Biotechnology (BIO), Glycoscience.
    Wang, Qi
    Bulone, Vincent
    KTH, School of Biotechnology (BIO), Glycoscience. Univ Adelaide, Australia.
    Tu, Yaoquan
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Insight into the adsorption profiles of the Saprolegnia monoica chitin synthase MIT domain on POPA and POPC membranes by molecular dynamics simulation studies2016In: Physical Chemistry, Chemical Physics - PCCP, ISSN 1463-9076, E-ISSN 1463-9084, Vol. 18, no 7, p. 5281-5290Article in journal (Refereed)
    Abstract [en]

    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.

  • 14.
    Kuang, Guanglin
    et al.
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Liang, Lijun
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Brown, Christian
    KTH, School of Biotechnology (BIO), Glycoscience.
    Wang, Qi
    Tu, Yaoquan
    Bulone, Vincent
    KTH, School of Biotechnology (BIO), Glycoscience.
    Tu, Yaoquan
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Insight into the adsorption profiles of the Saprolegnia practica chitin synthase MIT domain on POPA and POPC membranes by molecular dynamics simulation studiesManuscript (preprint) (Other academic)
  • 15.
    Kuang, Guanglin
    et al.
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Murugan, N. Arul
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Tu, Yaoquan
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Nordberg, Agneta
    Ågren, Hans
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Investigation of the Binding Profiles of AZD2184 and Thioflavin T with Amyloid-beta(1-42) Fibril by Molecular Docking and Molecular Dynamics Methods2015In: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 119, no 35, p. 11560-11567Article in journal (Refereed)
    Abstract [en]

    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.

  • 16.
    Kuang, Guanglin
    et al.
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Zhou, Yang
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Zou, Rongfeng
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Halldin, C.
    Nordberg, A.
    Långström, B.
    Ågren, Hans
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology. Siberian Federal University, Russian Federation.
    Tu, Yaoquan
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Characterization of the binding mode of the PET tracer [18F]ASEM to a chimera structure of the α7 nicotinic acetylcholine receptor2017In: RSC Advances, ISSN 2046-2069, E-ISSN 2046-2069, Vol. 7, no 32, p. 19787-19793Article in journal (Refereed)
    Abstract [en]

    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.

  • 17.
    Li, Junhao
    et al.
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Theoretical Chemistry and Biology. East China Univ Sci & Technol, Shanghai Key Lab New Drug Design, Sch Pharm, Shanghai, Peoples R China.
    Zhang, Hongxiao
    East China Univ Sci & Technol, Shanghai Key Lab New Drug Design, Sch Pharm, Shanghai, Peoples R China..
    Liu, Guixia
    East China Univ Sci & Technol, Shanghai Key Lab New Drug Design, Sch Pharm, Shanghai, Peoples R China..
    Tang, Yun
    East China Univ Sci & Technol, Shanghai Key Lab New Drug Design, Sch Pharm, Shanghai, Peoples R China..
    Tu, Yaoquan
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Theoretical Chemistry and Biology.
    Li, Weihua
    East China Univ Sci & Technol, Shanghai Key Lab New Drug Design, Sch Pharm, Shanghai, Peoples R China..
    Computational Insight Into Vitamin K-1 omega-Hydroxylation by Cytochrome P450 4F22018In: Frontiers in Pharmacology, ISSN 1663-9812, E-ISSN 1663-9812, Vol. 9, article id 1065Article in journal (Refereed)
    Abstract [en]

    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.

  • 18. Li, S.
    et al.
    Zou, Rongfeng
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Theoretical Chemistry and Biology.
    Tu, Yaoquan
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Theoretical Chemistry and Biology.
    Wu, J.
    Landry, M. P.
    Cholesterol-directed nanoparticle assemblies based on single amino acid peptide mutations activate cellular uptake and decrease tumor volume2017In: Chemical Science, ISSN 2041-6520, E-ISSN 2041-6539, Vol. 8, no 11, p. 7552-7559Article in journal (Refereed)
    Abstract [en]

    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.

  • 19.
    Li, Xin
    et al.
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Hede, Thomas
    Tu, Yaoquan
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Leck, Caroline
    Ågren, Hans
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Cloud droplet activation mechanisms of amino acid aerosol particles: insight from molecular dynamics simulations2013In: Tellus. Series B, Chemical and physical meteorology, ISSN 0280-6509, E-ISSN 1600-0889, Vol. 65, p. 65-Article in journal (Refereed)
    Abstract [en]

    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.

  • 20.
    Li, Xin
    et al.
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Leck, Caroline
    Sun, Lu
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Hede, Thomas
    Tu, Yaoquan
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Ågren, Hans
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Cross-Linked Polysaccharide Assemblies in Marine Gels: An Atomistic Simulation2013In: Journal of Physical Chemistry Letters, ISSN 1948-7185, E-ISSN 1948-7185, Vol. 4, no 16, p. 2637-2642Article in journal (Refereed)
    Abstract [en]

    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.

  • 21.
    Liang, Lijun
    et al.
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Cui, Peng
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Wang, Q.
    Wu, T.
    Ågren, Hans
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Tu, Yaoquan
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Theoretical study on key factors in DNA sequencing with graphene nanopores2013In: RSC Advances, ISSN 2046-2069, Vol. 3, no 7, p. 2445-2453Article in journal (Refereed)
    Abstract [en]

    Solid-state nanopores, in particular graphene nanopores, are believed to have promising applications in DNA sequencing. Many efforts have been made in this research area, the ultimate goal is to extend the DNA translocation time and to achieve single-base resolution. Unfortunately, several factors in DNA sequencing are still not well understood. In this paper, we report a study on the effects of two main factors, the salt concentration and the bias voltage, on the corresponding ionic current. We propose a theoretical model to explore the relationship between the occupied nanopore area and the current. We demonstrate that the DNA translocation time can be prolonged by decreasing the bias voltage and by properly narrowing the nanopore diameter. We find that the reduction of the blockade current depends on the ratio of the unoccupied nanopore area to the total nanopore area.

  • 22.
    Liang, Lijun
    et al.
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology. Zhejiang Univ, Peoples R China.
    Wang, Q.
    Ågren, Hans
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Tu, Yaoquan
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Computational studies of DNA sequencing with solid-state nanopores: Key issues and future prospects2014In: Frontiers in Chemistry, E-ISSN 2296-2646, Vol. 2, no FEB, article id 5Article in journal (Refereed)
    Abstract [en]

    Owing to the potential use for real personalized genome sequencing, DNA sequencing with solid-state nanopores has been investigated intensively in recent time. However, the area still confronts problems and challenges. In this work, we present a brief overview of computational studies of key issues in DNA sequencing with solid-state nanopores by addressing the progress made in the last few years. We also highlight future challenges and prospects for DNA sequencing using this technology.

  • 23.
    Liang, Lijun
    et al.
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology. Zhejiang University, China.
    Zhang, Zhisen
    Shen, Jiawei
    Zhe, Kong
    Wang, Qi
    Wu, Tao
    Ågren, Hans
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Tu, Yaoquan
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Theoretical studies on the dynamics of DNA fragment translocation through multilayer graphene nanopores2014In: RSC Advances, ISSN 2046-2069, E-ISSN 2046-2069, Vol. 4, no 92, p. 50494-50502Article in journal (Refereed)
    Abstract [en]

    Motivated by several potential advantages over common sequencing technologies, solid-state nanopores, in particular graphene nanopores, have recently been extensively explored as biosensor materials for DNA sequencing. Studies carried out on monolayer graphene nanopores aiming at single-base resolution have recently been extended to multilayer graphene (MLG) films, indicating that MLG nanopores are superior to their monolayer counterparts for DNA sequencing. However, the underlying dynamics and current change in the DNA translocation to thread MLG nanopores remain poorly understood. In this paper, we report a molecular dynamics study of DNA passing through graphene nanopores of different layers. We show that the DNA translocation time could be extended by increasing the graphene layers up to a moderate number (7) under a high electric field and that the current in DNA translocation undergoes a stepwise change upon DNA going through an MLG nanopore. A model is built to account for the relationship between the current change and the unoccupied volume of the MLG nanopore. We demonstrate that 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 could be improved by increasing the number of graphene layers in a certain range and by modifying the surface of the graphene nanopores.

  • 24.
    Liu, Kai
    et al.
    KTH, School of Biotechnology (BIO), Theoretical Chemistry.
    Wang, Yanhua
    KTH, School of Biotechnology (BIO), Theoretical Chemistry.
    Tu, Yaoquan
    KTH, School of Biotechnology (BIO), Theoretical Chemistry.
    Ågren, Hans
    KTH, School of Biotechnology (BIO), Theoretical Chemistry.
    Luo, Yi
    KTH, School of Biotechnology (BIO), Theoretical Chemistry.
    Aggregation effects on two-photon absorption spectra of octupolar molecules2007In: Journal of Chemical Physics, ISSN 0021-9606, E-ISSN 1089-7690, Vol. 127, no 2, p. 026101-Article in journal (Refereed)
    Abstract [en]

    Aggregation effects on two-photon absorption cross sections of an octupolar molecule, 1,3,5-triamino-2,4,6-trinitrobenzene, have been examined by means of density functional theory calculations in combination with molecular dynamic simulations. It is shown that this octupolar molecule becomes polar in solution and forms aggregates due to the presence of hydrogen bonding between molecules, which can induce a strong redshift of the charge-transfer state and significantly alter the TPA cross section.

  • 25.
    Liu, Kai
    et al.
    KTH, School of Biotechnology (BIO), Theoretical Chemistry.
    Wang, Yanhua
    Department of Physics, Linyi Normal University.
    Tu, Yaoquan
    KTH, School of Biotechnology (BIO), Theoretical Chemistry.
    Ågren, Hans
    KTH, School of Biotechnology (BIO), Theoretical Chemistry.
    Luo, Yi
    KTH, School of Biotechnology (BIO), Theoretical Chemistry.
    Two-photon absorption of hydrogen-bonded octupolar molecule clusters2008In: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 112, no 14, p. 4387-4392Article in journal (Refereed)
    Abstract [en]

    Charge-transfer octupolar molecules can form clusters in solution through intermolecular hydrogen bonds. In the present work we explore the role of such clustering on two-photon absorption (TPA) spectra assuming 1,3,5-triamino-2,4,6- trinitrobenzene (TATB) as a model system. Using density functional quadratic response theory we examine different cluster structures of TATB dimers, trimers, and tetramers taken from snapshots of molecular dynamics simulations. In comparison with the TPA spectrum of a monomer, significant red shifts of charge-transfer states are predicted for all chosen clusters, which mainly is the result of the distortion of the structures induced by the aggregation. The TPA spectra for dimers and trimers show strong conformation dependence, whereas they turn out to be more stable for tetramers. Enhancements of TPA absorption have also been found for clusters containing less distorted molecules connected by hydrogen bonds.

  • 26. Shi, Changchun
    et al.
    Kong, Zhe
    Sun, Tianyang
    Liang, Lijun
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology. Department of Chemistry, Soft Matter Research Center, Zhejiang University, China .
    Shen, Jiawei
    Zhao, Zhengyan
    Wang, Qi
    Kang, Zhengzhong
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology. Department of Chemistry, Soft Matter Research Center, Zhejiang University, China.
    Ågren, Hans
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Tu, Yaoquan
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Molecular dynamics simulations of DNA sequencing with graphene nanopores indicate that DNA bases can be identified by their translocation times2015In: RSC Advances, ISSN 2046-2069, E-ISSN 2046-2069, Vol. 5, no 13, p. 9389-9395Article in journal (Refereed)
    Abstract [en]

    The improvement of the resolution of DNA sequencing by nanopore technology is very important for its real-life application. In this paper, we report our work on using molecular dynamics simulation to study the dependence of DNA sequencing on the translocation time of DNA through a graphene nanopore, using the single-strand DNA fragment translocation through graphene nanopores with diameters down to similar to 2 nm as examples. We found that A, T, C, and G could be identified by the difference in the translocation time between different types of nucleotides through 2 nm graphene nanopores. In particular, the recognition of the graphene nanopore for different nucleotides can be greatly enhanced in a low electric field. Our study suggests that the recognition of a graphene nanopore by different nucleotides is the key factor for sequencing DNA by translocation time. Our study also indicates that the surface of a graphene nanopore can be modified to increase the recognition of nucleotides and to improve the resolution of DNA sequencing based on the DNA translocation time with a suitable electric field.

  • 27. Shi, Changchun
    et al.
    Zhe, Kong
    Sun, Tianyang
    Liang, Lijun
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology. Zhejiang University, China.
    Shen, Jiawei
    Zhao, Zhengyan
    Wang, Qi
    Kang, Zhengzhong
    Ågren, Hans
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Tu, Yaoquan
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Sequence dependence on DNA translocation time by graphene nanoporeManuscript (preprint) (Other academic)
  • 28.
    Sun, Lu
    et al.
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Hede, Thomas
    Tu, Yaoquan
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Leck, Caroline
    Ågren, Hans
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Combined Effect of Glycine and Sea Salt on Aerosol Cloud Droplet Activation Predicted by Molecular Dynamics Simulations2013In: Journal of Physical Chemistry A, ISSN 1089-5639, E-ISSN 1520-5215, Vol. 117, no 41, p. 10746-10752Article in journal (Refereed)
    Abstract [en]

    The present study illustrates the combined effect of organic and inorganic compounds on cloud droplet nucleation and activation processes representative for the marine environment. Amino acids and sea salt are common marine cloud condensation nuclei (CCN) which act as a prerequisite for growth of cloud droplets. The chemical and physical properties of these CCN play a key role for interfacial properties such as surface tension, which is important for the optical properties of clouds and for heterogeneous reactions. However, there is a lack of detailed information and in situ measurements of surface tension of such nanosized droplets. Here we present a study of the combined effect of zwitterionic glycine (ZGLY) and sea salt in nanosized water droplets using molecular dynamics simulations, where particular emphasis is placed on the surface tension for the nanosized droplets. The critical supersaturation is estimated by the Kohler equation. It is found that dissolved sea salt interacts with ZGLY through a water bridge and weakens the hydrogen bonds among ZGLYs, which has a significant effect on both surface tension and water vapor supersaturation. Clusters of glycine mixed with sea salt deliquesce more efficiently and have higher growth factors.

  • 29.
    Sun, Lu
    et al.
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Li, Xin
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Hede, Thomas
    Tu, Yaoquan
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Leck, Caroline
    Ågren, Hans
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Molecular Dynamics Simulations of the Surface Tension and Structure of Salt Solutions and Clusters2012In: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 116, no 10, p. 3198-3204Article in journal (Refereed)
    Abstract [en]

    Sodium halides, which are abundant in sea salt aerosols, affect the optical properties of aerosols and are active in heterogeneous reactions that cause ozone depletion and acid rain problems. Interfacial properties, including surface tension and halide anion distributions, are crucial issues in the study of the aerosols. We present results from molecular dynamics simulations of water solutions and clusters containing sodium halides with the interatomic interactions described by a conventional force field. The simulations reproduce experimental observations that sodium halides increase the surface tension with respect to pure water and that iodide anions reach the outermost layer of water clusters or solutions. It is found that the van der Waals interactions have an impact on the distribution of the halide anions and that a conventional force field with optimized parameters can model the surface tension of the salt solutions with reasonable accuracy.

  • 30.
    Sun, Lu
    et al.
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Li, Xin
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Hede, Thomas
    Stockholm University.
    Tu, Yaoquan
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Leck, Caroline
    Stockholm University.
    Ågren, Hans
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Molecular Dynamics Simulations Reveal the Assembly Mechanism of Polysaccharides in Marine Aerosols2014In: Physical Chemistry, Chemical Physics - PCCP, ISSN 1463-9076, E-ISSN 1463-9084, Vol. 16, no 47, p. 25935-25941Article in journal (Other academic)
    Abstract [en]

    The high Arctic marine environment has recently detected polymer gels in atmospheric aerosol particles and cloud water originating from the surface microlayer of the open leads within the pack ice area. These polysaccharide molecules are water insoluble but water solvated, highly surface-active and highly hydrated (99% water). In order to add to the understanding and to complement missing laboratory characterization of marine polymer gels we have in this work performed an atomistic study of the assembly process and interfacial properties of polysaccharides. Our study reveals a number of salient features of the microscopic process behind polysaccharide assembly into nanogels. With three- and four-repeating units the polysaccharides assemble into a cluster in 50 ns. The aggregates grow quicker by absorbing one or two polymers each time, depending on the unit length and the type of inter-bridging cation. Although both the hydrophobic and hydrophilic domains are contracted, the latter dominates distinctly upon the contraction of solvent accessible surface areas. The establishment of inter-chain hydrogen-bonds is the key to the assembly while ionic bridges can further promote aggregation. During the assembly of the more bent four-unit polymers, intra-chain hydrogen bonds are significantly diminished by Ca2+. Meanwhile, the percentage of Ca2+ acting as an ionic bridge is more eminent, highlighting the significance of Ca2+ ions for longer-chain polysaccharides. The aggregates are able to enhance surface tension more in the presence of Ca2+ than in the presence of Na+ owing to their more compact structure. These conclusions all demonstrate that studies of the present kind provide insight into the self-assembly process and interfacial properties of marine gels. We hope this understanding will keep up the interest in the complex and the fascinating relationship between marine microbiology, atmospheric aerosols, clouds and climate.

  • 31.
    Sun, Lu
    et al.
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Li, Xin
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Tu, Yaoquan
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Ågren, Hans
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Origin of Ion Selectivity at the Air/Water Interface2015In: Physical Chemistry, Chemical Physics - PCCP, ISSN 1463-9076, E-ISSN 1463-9084, Vol. 17, no 6, p. 4311-4318Article in journal (Refereed)
    Abstract [en]

    Among many characteristics of ions, their capability to accumulate at air/water interfaces is a particular issue that has been the subject of much research attention. For example, the accumulation of halide anions (Cl-, Br-, I-) at the water surface is of great importance to heterogeneous reactions that are of environmental concern. However, the actual mechanism that drives anions towards the air/water interface remains unclear. In this work, we have performed atomistic simulations using polarizable models to mimic ionic behavior under atmospheric conditions. We find that larger anions are abundant at the water surface and that the cations are pulled closer to the surface by the counterions. We propose that polarization effects stabilize the anions with large radii when approaching the surface. This energetically more favorable situation is caused by the fact that the more polarized anions at the surface attract water molecules more strongly. Of relevance is also the ordering of the surface water molecules with their hydrogen atoms pointing outwards which induce an external electronic field that leads to a different surface behavior of anions and cations. The water-water interaction is weakened by the distinct water-ion attraction, a point contradicting the proposition that F- is a kosmotrope. The simulation results thus allow us to obtain a more holistic understanding of the interfacial properties of ionic solutions and atmospheric aerosols.

  • 32.
    Sun, Xian-qiang
    et al.
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Chen, Lei
    Li, Yao-zong
    Li, Wei-hua
    Liu, Gui-xia
    Tu, Yao-quan
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Tang, Yun
    Structure-based ensemble-QSAR model: a novel approach to the study of the EGFR tyrosine kinase and its inhibitors2014In: Acta Pharmacologica Sinica, ISSN 1671-4083, E-ISSN 1745-7254, Vol. 35, no 2, p. 301-310Article in journal (Refereed)
    Abstract [en]

    Aim: To develop a novel 3D-QSAR approach for study of the epidermal growth factor receptor tyrosine kinase (EGFR TK) and its inhibitors. Methods: One hundred thirty nine EGFR TK inhibitors were classified into 3 clusters. Ensemble docking of these inhibitors with 19 EGFR TK crystal structures was performed. Three protein structures that showed the best recognition of each cluster were selected based on the docking results. Then, a novel QSAR (ensemble-QSAR) building method was developed based on the ligand conformations determined by the corresponding protein structures. Results: Compared with the 3D-QSAR model, in which the ligand conformations were determined by a single protein structure, ensemble-QSAR exhibited higher R2 (0.87) and Q2 (0.78) values and thus appeared to be a more reliable and better predictive model. Ensemble-QSAR was also able to more accurately describe the interactions between the target and the ligands. Conclusion: The novel ensemble-QSAR model built in this study outperforms the traditional 3D-QSAR model in rationality, and provides a good example of selecting suitable protein structures for docking prediction and for building structure-based QSAR using available protein structures.

  • 33.
    Sun, Xianqiang
    et al.
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Cheng, Jianxin
    Wang, Xu
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Tang, Yun
    Ågren, Hans
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Tu, Yaoquan
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Residues remote from the binding pocket control the antagonist selectivity towards the corticotropin-releasing factor receptor-12015In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 5, p. 8066-Article in journal (Refereed)
    Abstract [en]

    The corticotropin releasing factors receptor-1 and receptor-2 (CRF1R and CRF2R) are therapeutic targets for treating neurological diseases. Antagonists targeting CRF1R have been developed for the potential treatment of anxiety disorders and alcohol addiction. It has been found that antagonists targeting CRF1R always show high selectivity, although CRF1R and CRF2R share a very high rate of sequence identity. This has inspired us to study the origin of the selectivity of the antagonists. We have therefore built a homology model for CRF2R and carried out unbiased molecular dynamics and well-tempered metadynamics simulations for systems with the antagonist CP-376395 in CRF1R or CRF2R to address this issue. We found that the side chain of Tyr(6.63) forms a hydrogen bond with the residue remote from the binding pocket, which allows Tyr(6.63) to adopt different conformations in the two receptors and results in the presence or absence of a bottleneck controlling the antagonist binding to or dissociation from the receptors. The rotameric switch of the side chain of Tyr356(6.63) allows the breaking down of the bottleneck and is a perquisite for the dissociation of CP-376395 from CRF1R.

  • 34.
    Sun, Xianqiang
    et al.
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Laroch, Genevieve
    Wang, Xu
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Ågren, Hans
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Bowman, Gregory R.
    Giguõre, Patrick M.
    Tu, Yaoquan
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Propagation of the Allosteric Modulation Induced by Sodium in the delta-Opioid Receptor2017In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 23, no 19, p. 4615-4624Article in journal (Refereed)
    Abstract [en]

    Allosteric sodium in the helix bundle of a G protein-coupled receptor (GPCR) can modulate the receptor activation on the intracellular side. This phenomenon has confounded the GPCR community for decades. In this work, we present a theoretical model that reveals the mechanism of the allosteric modulation induced by sodium in the delta-opioid receptor. We found that the allosteric sodium ion exploits a distinct conformation of the key residue Trp2746.48 to propagate the modulation to helices 5 and 6, which further transmits along the helices and regulates their positions on the intracellular side. This mechanism is supported by subsequent functional assays. Remarkably, our results highlight the contrast between the allosteric effects towards two GPCR partners, the G protein and b-arrestin, as indicated by the fact that the allosteric modulation initiated by the sodium ion significantly affects the b-arrestin recruitment, while it alters the G protein signaling only moderately. We believe that the mechanism revealed in this work can be used to explain allosteric effects initiated by sodium in other GPCRs since the allosteric sodium is highly conserved across GPCRs. 

  • 35.
    Sun, Xianqiang
    et al.
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Ågren, Hans
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Tu, Yaoquan
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Computational investigation of G-proteins releasing from G-protein-coupled receptors2013In: Abstract of Papers of the American Chemical Society, ISSN 0065-7727, Vol. 246, p. 193-POLY-Article in journal (Other academic)
  • 36.
    Sun, Xianqiang
    et al.
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Ågren, Hans
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Tu, Yaoquan
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Function of the sodium ion in the activation of the δ-Opioid receptorManuscript (preprint) (Other academic)
  • 37.
    Sun, Xianqiang
    et al.
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Ågren, Hans
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Tu, Yaoquan
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Functional Water Molecules in Rhodopsin Activation2014In: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 118, no 37, p. 10863-10873Article in journal (Refereed)
    Abstract [en]

    G-protein-coupled receptors (GPCRs) are integral membrane proteins that mediate cellular response to an extensive variety of extracellular stimuli. Studies of rhodopsin, a prototype GPCR, have suggested that water plays an important role in mediating the activation of family A GPCRs. However, our understanding of the function of water molecules in the GPCR activation is still rather limited because resolving the functional water molecules solely based on the results from existing experiments is challenging. Using all-atom molecular dynamics simulations in combination with inhomogeneous fluid theory, we identify in this work the positioning of functional water molecules in the inactive state, the Meta II state, and the constitutive active state of rhodopsin, basing on the thermodynamic signatures of the water molecules. We find that one hydration site likely functions as a switch to regulate the distance between Glu181 and the Schiff base in the rhodopsin activation. We observe that water molecules adjacent to the "NpxxY" motif are not as stable in the Meta II state as in the inactive state as indicated by the thermodynamics signatures, and we rationalize that the behaviors of these water molecules are closely correlated with the rearrangement of the water-mediated hydrogen-bond network in the "NPxxY" motif, which is essential for mediating the activation of the receptor. We thereby propose a hypothesis of the water-mediated rhodopsin activation pathway.

  • 38.
    Sun, Xianqiang
    et al.
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Ågren, Hans
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Tu, Yaoquan
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Microsecond Molecular Dynamics Simulations Provide Insight into the Allosteric Mechanism of the Gs Protein Uncoupling from the beta(2) Adrenergic Receptor2014In: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 118, no 51, p. 14737-14744Article in journal (Refereed)
    Abstract [en]

    Experiments have revealed that in the beta(2) adrenergic receptor (beta(2)AR)-Gs protein complex the a subunit (G alpha s) of the Gs protein can adopt either an open conformation or a closed conformation. In the open conformation the Gs protein prefers to bind to the beta(2)AR, while in the closed conformation an uncoupling of the Gs protein from the beta(2)AR occurs. However, the mechanism that leads to such different behaviors of the Gs protein remains unclear. Here, we report results from microsecond molecular dynamics simulations and community network analysis of the beta(2)AR-Gs complex with G alpha s in the open and closed conformations. We observed that the complex is stabilized differently in the open and closed conformations. The community network analysis reveals that in the closed conformation there exists strong allosteric communication between the beta(2)AR and G beta gamma, mediated by G alpha s. We suggest that such high information flows are necessary for the Gs protein uncoupling from the beta(2)AR.

  • 39.
    Tu, Yaoquan
    et al.
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Costa Felicíssimo, Viviane
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Fernandes Guimarães, Freddy
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Ågren, Hans
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Gel’mukhanov, Faris
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Mechanical action of infrared light on atoms and molecules through a rectification of the electric force2009In: Physica Scripta, ISSN 0031-8949, E-ISSN 1402-4896, Vol. 80, no 5Article in journal (Refereed)
    Abstract [en]

    We report the mechanical action of infrared light on atoms and molecules based on the rectification of the electric force. This mechanism is qualitatively different from the conventional ways of controlling photochemistry. The rectification of the electric force originates from the synchronous charge transfer induced by the laser field. This brings about an opportunity to produce a site selective light-induced action, controlled by the tailored intense laser field, on atoms in molecules and clusters. The concept is illustrated by ab initio molecular dynamics simulations of the water hexamer.

  • 40.
    Tu, Yaoquan
    et al.
    KTH, School of Biotechnology (BIO), Theoretical Chemistry (closed 20110512).
    Jacobsson, Sven P.
    Laaksonen, Aatto
    Efficient ab initio tight-binding-like method for electronic structure calculations2006In: Physical Review B. Condensed Matter and Materials Physics, ISSN 1098-0121, E-ISSN 1550-235X, Vol. 74, no 20, p. 205104-Article in journal (Refereed)
    Abstract [en]

    A reliable and highly efficient ab initio tight-binding-like electronic structure calculation method is developed. The method starts from a similar approach outlined by Horsfield [Phys. Rev. B 56, 6594 (1997)], but in this work, the integral evaluations for the exchange-correlation matrix elements are achieved with reasonable accuracy by higher-order many-center expansions. All the integrals are obtained by the use of look-up tables and the efficiency of the calculation is further improved by optimizing the way to choose the integrals in the look-up tables. Calculations on molecular properties (such as equilibrium geometries, dipole moments, and the reaction energies for hydrogenation reactions for a series of molecules containing H, C, N, and O atoms) show that the method thus developed can be used as a general tool for the electronic structure calculations.

  • 41.
    Tu, Yaoquan
    et al.
    KTH, School of Biotechnology (BIO), Theoretical Chemistry (closed 20110512).
    Laaksonen, A.
    Towards Fast and Reliable Quantum Chemical Modelling of Macromolecules2006In: Lecture Notes in Computational Science and Engineering, ISSN 1439-7358, Vol. 49, p. 315-341Article in journal (Refereed)
    Abstract [en]

    Two possible routes to fast and reliable quantum chemical modelling and simulations of large macromolecules are outlined; a wave-function-based and an electron-densitybased. In the former method, the NDDO (Neglect of Diatomic Differential Overlap) approximation, a widely used basis for many semi-empirical molecular orbital approaches is examined and a new model, overcoming the inherent deficiencies in the NDDO model is proposed. In the new model, first order correction term is added to the electron-electron Coulomb interactions, thereby improving the balance between the core-electron and the electron-electron interactions. Using the new model, non-empirical calculations are performed showing that the total energies from this model are consistently slightly higher than those from corresponding ab initio calculation but closer to the ab initio results than when the standard NDDO is used. Before introducing the latter scheme, current ab initio tight-binding methods, developed from density functional theory are overviewed. Thereafter some improvements, especially those leading to faster and more accurate integral evaluations developed in our group, are presented. Aeries of calculations on sample molecules show that the results from our ab initio tight-binding method have nearly the same accuracy as those obtained from the corresponding frozen-core density functional calculations but at much faster speed. Both methods, the extended NDDO and the ab initio tight-binding, show a great potential as future schemes to model and simulate macromolecular systems at ab initio level of accuracy but at the speed comparable to today's semi-empirical calculations.

  • 42.
    Tu, Yaoquan
    et al.
    KTH, School of Biotechnology (BIO), Theoretical Chemistry (closed 20110512).
    Luo, Yi
    KTH, School of Biotechnology (BIO), Theoretical Chemistry (closed 20110512).
    Ågren, Hans
    KTH, School of Biotechnology (BIO), Theoretical Chemistry (closed 20110512).
    Can octupolar molecules be poled by an external electric field?2005In: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 109, no 35, p. 16730-16735Article in journal (Refereed)
    Abstract [en]

    Octupolar molecules are generally believed to be of potential use in developing nonlinear optical materials owing to the fact that they do not easily form molecular aggregates. This is often put against the conjectured drawback that electric fields have no poling, or ordering, effect for this class of molecules because of the lack of a permanent ground state dipole moment. In this paper, we analyze this notion in some detail and present results from molecular dynamics computer simulations of an ensemble of a prototypical octupolar molecule, the 1,3,5-triamino-2,4,6-trinitrobenzene (TATB) molecule, dissolved in chloroform. It is found that TATB molecules indeed show rather significant dipole moments in solutions because of the dual action of the thermal motions of the atoms and the strong intermolecular interactions. Applied electric fields accordingly show significant effects on the orientations of the molecular dipole moments. We also find that TATB molecules can aggregate because of the strong hydrogen-bonding interactions between the molecules, though they lack a static permanent dipole moment. Thus, the simulation results for TATB molecules in solution present us with a totally different notion about the collective properties of octupolar molecules. Taking account of quantum chemistry results, we found that the collective molecular nonlinear optical (NLO) properties are enhanced after the onset of the electric field, showing significant anisotropic characteristics.

  • 43.
    Tu, Yaoquan
    et al.
    KTH, School of Biotechnology (BIO), Theoretical Chemistry (closed 20110512).
    Luo, Yi
    KTH, School of Biotechnology (BIO), Theoretical Chemistry (closed 20110512).
    Ågren, Hans
    KTH, School of Biotechnology (BIO), Theoretical Chemistry (closed 20110512).
    Molecular dynamics simulations applied to electric field induced second harmonic generation in dipolar chromophore solutions2006In: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 110, no 18, p. 8971-8977Article in journal (Refereed)
    Abstract [en]

    Electric field induced second harmonic generation (EFISH) is an important experimental technique in extracting the first hyperpolarizability of an organic chromophore molecule. Such experiments are carried out in solutions with chromophore molecules dissolved in some common solvents. A known fact is that the first hyperpolarizabilities extracted from EFISH experiments are subject to the use of local field factors. In this work, we apply simulations to study the EFISH properties of chromophore solutions. By combining quantum chemistry calculations with the results derived from molecular dynamics simulations, we show how macroscopic EFISH properties can be modeled, using 4-(dimethylamino)-4'-nitroazobenzene dissolved in chloroform as a demonstration case. The focus of the study is on deriving accurate local field factors. We find that the local field approach applies very well to dipolar solutions, such as the one studied here, but that the local field factors derived are much smaller than the commonly used Onsager or Lorentz local field factors. Our study indicates that many of the reported first hyperpolarizabilities for dipolar molecules from EFISH experiments are most probably underestimated because the Onsager/Lorentz approach, commonly used in extracting the molecular first hyperpolarizability, neglects the effects of the shapes of dipolar chromophore molecules on the local field factors.

  • 44.
    Tu, Yaoquan
    et al.
    KTH, School of Biotechnology (BIO), Theoretical Chemistry (closed 20110512).
    Nilsson, Lennart
    Laaksonen, Aatto
    A highly efficient Ab initio tight-binding-like approximate density-functional quantum mechanical method2007In: Applied Parallel Computing: State Of The Art In Scientific Computing / [ed] Kagstrom, B; Elmroth, E; Dongarra, J; Wasniewski, J, 2007, Vol. 4699, p. 100-108Conference paper (Refereed)
    Abstract [en]

    A highly efficient ab initio tight-binding-like approximate density-functional quantum mechanical method has recently been developed by us. In this method, the integrals related to the exchange-correlation part are obtained by higher order many-center expansions and all the integrals can be obtained by the interpolation of the look-up tables. The speed of the calculation is also enhanced by using a better way to choose the integrals in the look-up tables. It is shown that the calculated molecular equilibrium geometries and the reaction energies for hydrogenation reactions are very close to those from the usual density functional theory calculations.

  • 45.
    Wang, Xu
    et al.
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Granata, Daniele
    Sun, Xianqiang
    Wang, Yong
    Ågren, Hans
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Tu, Yaoquan
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Coupled Folding and Binding of the Intrinsically Disordered AICD Peptide in the Presence of the Fe65-PTB2 ProteinArticle in journal (Refereed)
    Abstract [en]

    Intrinsically disordered proteins (IDPs) exert important cellular functions. Many IDPs that are partially or completely disordered in free states fold into well-defined tertiary structures upon binding to their targets, an association process involving coupled folding and binding. Although many biophysical and computational approaches have been applied to study coupled folding and binding reactions over the past decade, an atomic-level description of the binding of IDPs and the underlying mechanisms still represents a major challenge. Here, we present results of atomistic simulations of a natively unfolded peptide AICD binding to its target Fe65-PTB2. By bias-exchange metadynamics we computed a three-dimensional free-energy landscape for the binding process and identified several local minima corresponding to distinct intermediate states. The associated free energy is in good agreement with experimental results. By kinetic Monte Carlo simulations, we obtained two possible paths for AICD binding to Fe65-PTB2 that both confirm that the identified intermediates are on-path. We described the binding process with atomistic details, and found that the partially folded AICD peptide first approaches the Fe65-PTB2 protein to form different diffusion encounter complexes, which then evolve through multiple intermediates to the final native state. The binding of AICD proceeds via a kinetic divide-and-conquer strategy by which AICD folds in a stepwise fashion. We propose that the interaction of AICD with the target takes place via an induced fit mechanism. 

  • 46.
    Wang, Xu
    et al.
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Sun, Xianqiang
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Kuang, Guanglin
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Ågren, Hans
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Tu, Yaoquan
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    A theoretical study on the molecular determinants of the affibody protein ZAbeta3 bound to an amyloid beta peptide.2015In: Physical Chemistry, Chemical Physics - PCCP, ISSN 1463-9076, E-ISSN 1463-9084, Vol. 17, no 26, p. 16886-16893Article in journal (Refereed)
    Abstract [en]

    Amyloid beta (A beta) peptides are small cleavage products of the amyloid precursor protein. Aggregates of A beta peptides are thought to be linked with Alzheimer's and other neurodegenerative diseases. Strategies aimed at inhibiting amyloid formation and promoting A beta clearance have been proposed and investigated in in vitro experiments and in vivo therapies. A recent study indicated that a novel affibody protein Z(A beta 3), which binds to an A beta 40 monomer with a binding affinity of 17 nM, is able to prevent the aggregation of A beta 40. However, little is known about the energetic contribution of each residue in Z(A beta 3) to the formation of the (Z(A beta 3))(2):A beta complex. To address this issue, we carried out unbiased molecular dynamics simulations and molecular mechanics Poisson-Boltzmann surface area calculations. Through the per-residue decomposition scheme, we identified that the van der Waals interactions between the hydrophobic residues of (Z(A beta 3))(2) and those at the exterior and interior faces of A beta are the main contributors to the binding of (Z(A beta 3))(2) to A beta. Computational alanine scanning identified 5 hot spots, all residing in the binding interface and contributing to the binding of (Z(A beta 3))(2) to A beta through the hydrophobic effect. In addition, the amide hydrogen bonds in the 4-strand beta-sheet and the pi-pi stacking were also analyzed. Overall, our study provides a theoretical basis for future experimental improvement of the Z(A beta 3) peptide binding to A beta.

  • 47.
    Wang, Yan
    et al.
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Bergenstråhle-Wohlert, Malin
    KTH, School of Chemical Science and Engineering (CHE), Fibre and Polymer Technology. KTH, School of Chemical Science and Engineering (CHE), Centres, Wallenberg Wood Science Center.
    Tu, Yaoquan
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Ågren, Hans
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Berglund, Lars A.
    KTH, School of Chemical Science and Engineering (CHE), Fibre and Polymer Technology. KTH, School of Chemical Science and Engineering (CHE), Centres, Wallenberg Wood Science Center.
    Wohlert, Jakob
    KTH, School of Chemical Science and Engineering (CHE), Fibre and Polymer Technology. KTH, School of Chemical Science and Engineering (CHE), Centres, Wallenberg Wood Science Center.
    Swelling and dimensional stability of xyloglucan/montmorillonite nanocomposites in moist conditions from molecular dynamics simulations2017In: Computational Materials Science, ISSN 0927-0256, Vol. 128, p. 191-197Article in journal (Refereed)
    Abstract [en]

    Nacre-mimetic biocomposites made from the combination of montmorillonite clay and the hemicellulose xyloglucan give materials that retain much of their material properties even at high relative humidity. Here, a model composite system consisting of two clay platelets intercalated by xyloglucan oligomers was studied at different levels of hydration using molecular dynamics simulations, and compared to the pure clay. It was found that xyloglucan inhibits swelling of the clay at low water contents by promoting the formation of nano-sized voids that fill with water without affecting the material's dimensions. At higher water contents the XG itself swells, but at the same time maintaining contact with both platelets across the gallery, thereby acting as a physical cross-linker in a manner similar to the role of XG in the plant cell wall.

  • 48.
    Wang, Yan
    et al.
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Wohlert, Jakob
    KTH, School of Chemical Science and Engineering (CHE), Fibre and Polymer Technology. KTH, School of Chemical Science and Engineering (CHE), Centres, Wallenberg Wood Science Center.
    Bergenstråhle-Wohlert, Malin
    KTH, School of Chemical Science and Engineering (CHE), Fibre and Polymer Technology. KTH, School of Chemical Science and Engineering (CHE), Centres, Wallenberg Wood Science Center.
    Kochumalayil, Joby J.
    KTH, School of Chemical Science and Engineering (CHE), Fibre and Polymer Technology. KTH, School of Chemical Science and Engineering (CHE), Centres, Wallenberg Wood Science Center.
    Berglund, Lars A.
    KTH, School of Chemical Science and Engineering (CHE), Fibre and Polymer Technology. KTH, School of Chemical Science and Engineering (CHE), Centres, Wallenberg Wood Science Center.
    Tu, Yaoquan
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Ågren, Hans
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Molecular Adhesion at Clay Nanocomposite Interfaces Depends on Counterion Hydration-Molecular Dynamics Simulation of Montmorillonite/Xyloglucan2015In: Biomacromolecules, ISSN 1525-7797, E-ISSN 1526-4602, Vol. 16, no 1, p. 257-265Article in journal (Refereed)
    Abstract [en]

    Nacre-mimetic clay/polymer nanocomposites with clay platelet orientation parallel to the film surface show interesting gas barrier and mechanical properties. In moist conditions, interfacial adhesion is lowered and mechanical properties are reduced. Molecular dynamic simulations (MD) have been performed to investigate the effects of counterions on molecular adhesion at montmorillonite clay (Mnt)-xyloglucan (XG) interfaces. We focus on the role of monovalent cations K+, Na+, and Li+ and the divalent cation Ca2+ for mediating and stabilizing the Mnt/XG complex formation. The conformation of adsorbed XG is strongly influenced by the choice of counterion and so is the simulated work of adhesion. Free energy profiles that are used to estimate molecular adhesion show stronger interaction between XG and clay in the monovalent cation system than in divalent cation system, following a decreasing order of K-Mnt, Na-Mnt, Li-Mnt, and Ca-Mnt. The Mnt clay hydrates differently in the presence of different counterions, leading to a chemical potential of water that is highest in the case of K-Mnt, followed by Na-Mnt and Li-Mnt, and lowest in the case of Ca-Mnt. This means that water is most easily displaced from the interface in the case of K-Mnt, which contributes to the relatively high work of adhesion. In all systems, the penalty of replacing polymer with water at the interface gives a positive contribution to the work of adhesion of between 19 and 35%. Our work confirms the important role of counterions in mediating the adsorption of biopolymer XG to Mnt clays and predicts potassium or sodium as the best choice of counterions for a Mnt-based biocomposite design.

  • 49.
    Wang, Yan
    et al.
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Wohlert, Jakob
    KTH, School of Chemical Science and Engineering (CHE), Fibre and Polymer Technology. KTH, School of Chemical Science and Engineering (CHE), Centres, Wallenberg Wood Science Center.
    Bergenstråhle-Wohlert, Malin
    KTH, School of Chemical Science and Engineering (CHE), Fibre and Polymer Technology. KTH, School of Chemical Science and Engineering (CHE), Centres, Wallenberg Wood Science Center.
    Tu, Yaoquan
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Ågren, Hans
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Hydration and dimensional stability of the intercalated galleries in xyloglucan/montmorillonite nanocomposites studied by molecular dynamics simulationsManuscript (preprint) (Other academic)
    Abstract [en]

    The outstanding properties of biological composite nacre materials have for a long time inspired research and development of man-made bionanocomposites. One of the most recent nacre-mimetic bionanocomposites comprising xygloglucan (XG) and montmorillonite (Mnt) clay has been investigated by related model systems through Molecular dynamics (MD) simulations. The expansion of the inter-gallery of the XG-Mnt composites when exposed to water, has been found to be a key issue for the material property. In order to shed light on the mechanism for this swelling behavior we have investigated the relation between the hydration and the dimensional stability of the inter-gallery in XG-Mnt composites, exploring also the role of the dynamic state of the polymer XG for the dimensional change. We find that at a hydration level below 50%, XG-Mnt possesses good dimensional stability, suggesting a constant performance of the material, while at a hydration level of 75%, the expansion ratio of the composite is found to be slightly smaller than the swelling of Mnt clay. At the four-layer hydrate formation with a hydration level of 100%, the swelling ratios of clay and the2composite reach the same value, suggesting a critical point of losing dimensional stability. We conclude that the strong adhesion between the polymer XG and the Mnt clay is the main driving force for the preservation of the stability at lower hydration conditions, while the dynamics of the XG polymer is related to the losing of dimensional stability for the composite at higher hydration levels. The ramification of these results in terms of moisture sensitivity of the material is briefly discussed.

  • 50.
    Wang, Yan
    et al.
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Wohlert, Jakob
    KTH, School of Chemical Science and Engineering (CHE), Fibre and Polymer Technology. KTH, School of Chemical Science and Engineering (CHE), Centres, Wallenberg Wood Science Center.
    Bergenstråhle-Wohlert, Malin
    KTH, School of Chemical Science and Engineering (CHE), Fibre and Polymer Technology. KTH, School of Chemical Science and Engineering (CHE), Centres, Wallenberg Wood Science Center.
    Tu, Yaoquan
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Ågren, Hans
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Molecular mechanisms for the adhesion of chitin and chitosan to montmorillonite clayManuscript (preprint) (Other academic)
    Abstract [en]

    Molecular dynamics simulations have been performed to investigate molecular adhesion of chitin and chitosan oligomers to montmorillonite (Mnt) clay at different degrees of acetylation (DA, 0%, 20%, 40%, 60%, 80% and 100%) and different degree of protonation (DPr, 0%, 50%, 100% mimicking pH > 6.5, pH = 6.5, pH < 4, respectively) under fully hydrated conditions. Although the Mnt surface is negatively charged and a variation in DA also implies going from a positively charged oligomer at DA = 0% to a neutral oligomer at DA = 100%, the simulations show unexpectedly variation of the total molecular adhesion as a function of DA. From our analysis we propose that this quantitatively similar adhesion arise from two different mechanisms. At low DA, the oligomer is rich in positively charged amino groups interacting strongly with the negatively charged surface by direct electrostatic interaction. On the other hand, at high DA, electrically neutral acetyl groups are strongly correlated with the Na+ counter ions, which are in all cases stuck at the surface and the counter ions seem to act as ‘glue’ between the acetyl groups and the Mnt. However, when protonation was decreased, adhesion was significantly lowered. The reason is conclued by differences in charge distributions of the respective functional groups. A further investigation on the intramolecular hydrogen bonds formed in CHT or CHS shows that the adsorbed conformation of the polymer is also highly affected by DA. This work provides fundamental insights into adhesion mechanisms and is, of potential importance for the development of polymer-clay based composite materials.

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