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  • 13001.
    Åqvist, J., Fothergill, M. & Warshel, A.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Computer Simulation of the CO2/HCO3- Interconversion Step in Human Carbonic Anhydrase I1993In: J. Am. Chem. Soc., Vol. 115, p. 631-Article in journal (Refereed)
  • 13002.
    Åqvist, J., Kolmodin, K., Florian, J. & Warshel, A.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Mechanistic Alternatives in Phosphate Ester Hydrolysis1999In: Chemistry & Biology, Vol. 6, p. R71-Article in journal (Refereed)
  • 13003.
    Åqvist, J., Luzhkov, V.B. & Brandsdal, B.O.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Ligand Binding Affinities from MD Simulations2002In: Acc. Chem. Res., Vol. 35, p. 358-Article in journal (Refereed)
  • 13004.
    Åqvist, J., Medina, C. & Samuelsson, J.-E.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology.
    A New Method for Predicting Binding Affinity in Computer-Aided Drug Design1994In: Protein Eng., Vol. 7, p. 385-Article in journal (Refereed)
  • 13005.
    Åqvist, J.
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Warshel, A.
    Simulation of Enzyme Reactions Using Valence Bond Force Fields and Other Hybrid Quantum/Classical Approaches1993In: Chemical ReviewsArticle in journal (Refereed)
  • 13006.
    Åqvist, J
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology, Structural Molecular Biology.
    Wennerström, P
    Nervall, M
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology, Structural Molecular Biology.
    Bjelic, S
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology, Structural Molecular Biology.
    Brandsdal, B
    Molecular Dynamics Simulations of Water and Biomolecules with a Monte Carlo Constant Pressure Algorithm2004In: Chem. Phys. Lett., Vol. 384, p. 288.-Article in journal (Refereed)
  • 13007.
    Åqvist, Johan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics.
    Cold Adaptation of Triosephosphate Isomerase2017In: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 56, no 32, p. 4169-4176Article in journal (Refereed)
    Abstract [en]

    The main problem for enzymes from psychrophilic species, which need to work near the freezing point of liquid water, is the exponential decay of reaction rates as the temperature is decreased. Cold-adapted enzymes have solved this problem by shifting the activation enthalpy-entropy balance for the catalyzed reaction compared to those of their mesophilic orthologs. To understand the structural basis of this universal feature, it is necessary to examine pairs of such orthologous enzymes, with known three-dimensional structures, at the microscopic level. Here, we use molecular dynamics free energy calculations in combination with the empirical valence bond method to evaluate the temperature dependence of the activation free energy for differently adapted triosephosphate isomerases. The results show that the enzyme from the psychrophilic bacterium Vibrio marinus indeed displays the characteristic shift in enthalpy-entropy balance, compared to that of the yeast ortholog. The origin of this effect is found to be located in a few surface-exposed protein loops that show differential mobilities in the two enzymes. Key mutations render these loops more mobile in the cold-adapted triosephosphate isomerase, which explains both the reduced activation enthalpy contribution from the protein surface and the lower thermostability.

  • 13008.
    Åqvist, Johan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics.
    Computing the temperature dependence of chemical reactions inside and outside of living things2015In: European Biophysics Journal, ISSN 0175-7571, E-ISSN 1432-1017, Vol. 44, p. S160-S160Article in journal (Other academic)
  • 13009.
    Åqvist, Johan
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics.
    Isaksen, Geir Villy
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics. Univ Tromso, Dept Chem, Ctr Theoret & Computat Chem, N-9037 Tromso, Norway..
    Brandsdal, Bjorn Olav
    Univ Tromso, Dept Chem, Ctr Theoret & Computat Chem, N-9037 Tromso, Norway..
    Computation of enzyme cold adaptation2017In: Nature Reviews Chemistry, E-ISSN 2397-3358, Vol. 1, no 7, article id UNSP 0051Article, review/survey (Refereed)
    Abstract [en]

    Earth has several environments that are potentially hostile to life. The survival of organisms has required the expression of proteins that are adapted to function under extreme temperature, pH, pressure or ionic strength. However, the origin of such adaptations remains, in most cases, an open question. This Review presents a detailed analysis of the specialized enzymes that are able to maintain high catalytic rates at low temperatures and highlights the important role that computational studies have in uncovering the evolutionary principles behind the cold adaptation of enzymes. Although often highly homologous to their mesophilic counterparts, these cold-adapted enzymes have characteristic and universal properties that reflect their evolutionary optimization. In addition to exhibiting maximum reaction rates at lower temperatures, cold-adapted enzymes are more heat-labile and their catalytic mechanisms have distinct signatures in terms of the thermodynamic activation parameters. The structural origins of these properties have been elusive but are hypothesized to be related to protein flexibility.

  • 13010.
    Åqvist, Johan
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
    Kamerlin, Lynn Shina Caroline
    The Conformation of a Catalytic Loop Is Central to GTPase Activity on the Ribosome2015In: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 54, no 2, p. 546-556Article in journal (Refereed)
    Abstract [en]

    The translational GTPases hydrolyze GTP on the ribosome at several stages of the protein synthesis cycle. Because of the strong conservation of their catalytic center, these enzymes are expected to operate through a universal hydrolysis mechanism, in which a critical histidine residue together with the sarcin-ricin loop of the large ribosomal subunit is necessary for GTPase activation. Here we examine different possible pathways for GTP hydrolysis by EF-Tu through extensive computer simulations. We show that a conformational change of the peptide plane preceding this histidine has a decisive effect on the energetics of the reaction. This transition was predicted earlier by us and has recently been confirmed experimentally. It is found to promote early proton transfer from water to the gamma-phosphate group of GTP, followed by nucleophilic attack by hydroxide ion. The calculated reaction energetics is in good agreement with available kinetic data, for both wild-type and mutant versions of EF-Tu, and indicates that the latter may enforce a change in mechanism toward more concerted pathways.

  • 13011.
    Åqvist, Johan
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Kazemi, Masoud
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Isaksen, Geir Villy
    Univ Tromso, Dept Chem, Ctr Theoret Computat Chem, N-9037 Tromso, Norway..
    Brandsdal, Bjorn Olav
    Univ Tromso, Dept Chem, Ctr Theoret Computat Chem, N-9037 Tromso, Norway..
    Entropy and Enzyme Catalysis2017In: Accounts of Chemical Research, ISSN 0001-4842, E-ISSN 1520-4898, Vol. 50, no 2, p. 199-207Article, review/survey (Refereed)
    Abstract [en]

    CONSPECTUS: The role played by entropy for the enormous rate enhancement achieved by enzymes has been debated for many decades. There are, for example, several confirmed cases where the activation free energy is reduced by around 10 kcal/mol due to entropic effects, corresponding to a rate enhancement of similar to 10(7) compared to the uncatalyzed reaction. However, despite substantial efforts from both the experimental and theoretical side, no real consensus has been reached regarding the origin of such large entropic contributions to enzyme catalysis. Another remarkable instance of entropic effects is found in enzymes that are adapted by evolution to work at low temperatures, near the freezing point of water. These cold-adapted enzymes invariably show a more negative entropy and a lower enthalpy of activation than their mesophilic orthologs, which counteracts the exponential damping of reaction rates at lower temperature. The structural origin of this universal phenomenon has, however, remained elusive. The basic problem with connecting macroscopic thermodynamic quantities, such as activation entropy and enthalpy derived from Arrhenius plots, to the 3D protein structure is that the underlying detailed (microscopic) energetics is essentially inaccessible to experiment. Moreover, attempts to calculate entropy contributions by computer simulations have mostly focused only on substrate entropies, which do not provide the full picture. We have recently devised a new approach for accessing thermodynamic activation parameters of both enzyme and solution reactions from computer simulations, which turns out to be very successful. This method is analogous to the experimental Arrhenius plots and directly evaluates the temperature dependence of calculated reaction free energy profiles. Hence, by extensive molecular dynamics simulations and calculations of up to thousands of independent free energy profiles, we are able to extract activation parameters with sufficient precision for making direct comparisons to experiment. We show here that the agreement with the measured quantities, for both enzyme catalyzed and spontaneous solution reactions, is quite remarkable. Importantly, we can now address some of the most spectacular entropy effects in enzymes and clarify their detailed microscopic origin. Herein, we discuss as examples the conversion of cytidine to uridine catalyzed by cytidine deaminase and reactions taking place on the ribosome, namely, peptide bond formation and GTP hydrolysis by elongation factor Tu. It turns out that the large entropy contributions to catalysis in these cases can now be rationalized by our computational approach. Finally, we address the problem of cold adaptation of enzyme reaction rates and prove by computational experiments that the universal activation enthalpy entropy phenomenon originates from mechanical properties of the outer protein surface.

  • 13012.
    Åqvist, Johan
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Molecular Biology.
    Mowbray, Sherry L.
    Sugar Recognition by a Glucose/Galactose Receptor: Evaluation of Binding Energetics from Molecular Dynamics Simulations1995In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 270, no 17, p. 9978-9981Article in journal (Refereed)
    Abstract [en]

    A new theoretical method for free energy calculations is used to compute the absolute binding constants for β-D-glucose and methyl-β-D-galactoside to the periplasmic glucose/galactose receptor from Salmonella typhimurium. The computer simulation results agree well with available experimental data and make it possible to assess the sources of both the high affinity as well as the specificity for glucose. It was found that the major contribution to the binding energy comes from electrostatic interactions and particularly hydrogen bonds of the charge-dipole type. We also predict the structure of the complex with methyl-galactoside as this has not yet been experimentally determined.

  • 13013.
    Åström, Anders
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Medical Genetics.
    Åström, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Medical Genetics.
    Virtanen, Anders
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Medical Genetics.
    A simple procedure for isolation of eukaryotic mRNA polyadenylation factors1991In: European Journal of Biochemistry, ISSN 0014-2956, E-ISSN 1432-1033, Vol. 202, no 3, p. 765-773Article in journal (Refereed)
    Abstract [en]

    We have devised a simple chromatographic procedure which isolates five polyadenylation factors that are required for polyadenylation of eukaryotic mRNA. The factors were separated from each other by fractionation of HeLa cell nuclear extract in two consecutive chromatographic steps. RNA cleavage at the L3 polyadenylation site of human adenovirus 2 required at least four factors. Addition of adenosine residues required only two of these factors. The fractionation procedure separates two components that are both likely to be poly(A) polymerases. The candidate poly(A) polymerases were interchangeable and participated during both RNA cleavage and adenosine addition. They were discriminated from each other by chromatographic properties, heat sensitivity and divalent cation requirement. We have compared our data with published information and have been able to correlate the activities that we have isolated to previously identified polyadenylation factors. However, we have not been able to assign one of the candidate poly(A) polymerases to a previously identified poly(A) polymerase. This simple fractionation procedure can be used for generating an in vitro reconstituted system for polyadenylation within a short period of time.

  • 13014.
    Åström, Jonas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Medical Genetics.
    Åström, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Medical Genetics.
    Virtanen, Anders
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Medical Genetics.
    In vitro deadenylation of mammalian mRNA by a HeLa cell 3' exonuclease1991In: EMBO Journal, ISSN 0261-4189, E-ISSN 1460-2075, Vol. 10, no 10, p. 3067-3071Article in journal (Refereed)
    Abstract [en]

    We have identified a 3' exonuclease in HeLa cell extracts which deadenylates mammalian mRNA and leaves the mRNA body intact after poly(A) removal. Only homopolymeric adenosine tails located at the 3' end were efficiently removed by the exonuclease. The poly(A) removing activity did not require any specific sequences in the mRNA body either for poly(A) removal or for accumulation of the deadenylated mRNA. We conclude that the poly(A) removing activity is a 3' exonuclease since (i) reaction intermediates gradually lose the poly(A) tail, (ii) degradation is prevented by the presence of a cordycepin residue at the 3' end and (iii) RNAs having internally located poly(A) stretches are poor substrates for degradation. The possible involvement of the poly(A) removing enzyme in regulating mRNA translation and stability is discussed.

  • 13015.
    Åström, Jonas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Medical Genetics.
    Åström, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Medical Genetics.
    Virtanen, Anders
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Properties of a HeLa cell 3' exonuclease specific for degrading poly(A) tails of mammalian mRNA.1992In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 267, no 25, p. 18154-18159Article in journal (Refereed)
    Abstract [en]

    A HeLa cell 3'-exonuclease with properties of a mammalian mRNA poly(A) tail-removing enzyme has been characterized. The exonuclease shows high specificity for the poly(A) tail, and it is single strand-specific and requires a 3'-hydroxyl group for its activity. During degradation 5'-AMP is liberated as a product, and a 3'-OH group is left on the last adenosine residue of the remaining poly(A) tail. The activity is inhibited by 5'-AMP and can be competed by poly(A)-containing mRNA or poly(A). Based on these findings we propose a reaction pathway for poly(A) tail removal catalyzed by the HeLa cell poly(A) tail-specific 3' exonuclease.

  • 13016.
    Ödeen, Anders
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Evolutionary Biology.
    Effects of Post-Glacial Range Expansions and Population Bottlenecks on Species Richness2001Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    This thesis relates modern speciation theory to the effects of sudden changes in the range and size of populations. Special reference is made to the climatic oscillations during the Quaternary ice ages. A meta-analysis of laboratory experiments showed that support for allopatric speciation is weak, especially for the peripatric type of allopatric speciation. Furthermore, factors traditionally believed to increase the likelihood of speciation have had little effect on the generation of reproductive isolation in speciation experiments. However, the method of testing reproductive isolation appeared important, in the sense that experimentally derived sister populations were likely to demonstrate reproductive isolation from each other but not from the unaffected mother population. Raw data from mating tests showed that the poor isolation between mother and daughter populations was an effect of asymmetric mate preferences towards males from the mother population. This suggests that peripatric speciation can be effective in generating reproductive isolation between sister populations. The proposed mechanism is that males become less attractive to females by losing certain secondary sexual traits during population bottlenecks, and that females shift their preferences towards other male traits. Support for this mode of speciation is found in the widespread bird genus Motacilla (wagtails). This genus is characterised by extensive plumage variation and contains a large number of widely distributed taxa in the northern parts of its distribution. This thesis shows that taxonomic diversity of wagtails is inversely related to complexity in song and to diversity in molecular and mitochondrial markers. The northern taxa seem to be descendants of southern populations, which were subjected to bottlenecks during expansions into re-opened habitats after the last ice age. The bottlenecks would not only reduce genetic diversity but also inhibit cultural transmission of song to the leading edge of colonisers, allowing sexual selection on other traits, such as plumage. Rapid plumage differentiation among wagtail taxa appears to be a recurrent process and has lead to convergent evolution, making the currently recognised species Motacilla flava (Yellow Wagtail) polyphyletic.

  • 13017.
    Ödeen, Anders
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Evolutionary Biology. Department of Ecology and Evolution, Animal Ecology. Zooekologi.
    Björklund, Mats
    Department of Ecology and Evolution, Animal Ecology.
    Dynamics in the evolution of sexual traits: losses and gains, radiation and convergence in yellow wagtails (Motacilla flava)2003In: Molecular Ecology, ISSN 09621083, Vol. 12, no 8, p. 2113-2130Article in journal (Refereed)
    Abstract [en]

    We analyse patterns of genetic diversity and song complexity in the Palaearctic yellow wagtail (Motacilla flava), a highly polytypic species complex. Mitochondrial and nuclear DNA show that the complex is polyphyletic, despite parallel plumage variation i

  • 13018.
    Ödeen, Anders
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Evolution, Animal Ecology.
    Hart, Nathan S.
    School of Biomedical Sciences, The University of Queensland, Brisbane.
    Håstad, Olle
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Evolutionary Organism Biology.
    Assessing the use of genomic DNA as a predictor of the maximum absorbance wavelength of avian SWS1 opsin visual pigments2009In: Journal of Comparative Physiology A. Sensory, neural, and behavioral physiology, ISSN 0340-7594, E-ISSN 1432-1351, Vol. 195, no 2, p. 167-173Article in journal (Refereed)
    Abstract [en]

    Recently, in vitro mutation studies have made it possible to predict the wavelengths of maximum absorbance (λmax) of avian UV/violet sensitive visual pigments (SWS1) from the identity of a few key amino acid residues in the opsin gene. Given that the absorbance spectrum of a cone's visual pigment and of its pigmented oil droplet can be predicted from just the λmax, it may become possible to predict the entire spectral sensitivity of a bird using genetic samples from live birds or museum specimens. However, whilst this concept is attractive, it must be validated to assess the reliability of the predictions of λmax from opsin amino acid sequences. In this paper, we have obtained partial sequences covering three of the known spectral tuning sites in the SWS1 opsin and predicted λmax of all bird species for which the spectral absorbance has been measured using microspectrophotometry. Our results validate the use of molecular data from genomic DNA to predict the gross differences in λmax between the violet- and ultraviolet-sensitive subtypes of SWS1 opsin. Additionally, we demonstrate that a bird, the bobolink Dolichonyx oryzivorus L., can have more than one SWS1 visual pigment in its retina.

  • 13019. Ödeen, Anders
    et al.
    Håstad, Olle
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Evolutionary Biology, Animal Ecology.
    Complex Distribution of Avian Color Vision Systems Revealed by Sequencing the SWS1 Opsin from Total DNA2003In: Molecular Biology and Evolution, ISSN 0737-4038, Vol. 20, no 6, p. 855–861-Article in journal (Refereed)
  • 13020.
    Ödeen, Anders
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Evolutionary Biology.
    Håstad, Olle
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Evolutionary Biology.
    Complex distribution of avian color vision systems revealed by sequencing the SWS1 opsin from total DNA2003In: Molecular Biology and Evolution, ISSN 0737-4038, Vol. 20, no 6, p. 855-861Article in journal (Refereed)
    Abstract [en]

    To gain insights into the evolution and ecology of visually acute animals such as birds, biologists often need to understand how these animals perceive colors. This poses a problem, since the human eye is of a different design than that of most other anim

  • 13021.
    Ödeen, Anders
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Evolution, Animal Ecology.
    Håstad, Olle
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Evolutionary Organism Biology.
    New Primers for the Avian SWS1 Pigment Opsin Gene Reveal New Amino Acid Configurations in Spectral Sensitivity Tuning Sites2009In: Journal of Heredity, ISSN 0022-1503, E-ISSN 1465-7333, Vol. 100, no 6, p. 784-789Article in journal (Refereed)
    Abstract [en]

    Recently, polymerase chain reaction-based estimates of visual pigment spectral tuning from genomic DNA have offered an alternative to the authoritative but rather slow and complicated retinal microspectrophotometry method. The genomic DNA method involves sequencing a fragment of the short-wavelength sensitive pigment, type 1 (SWS1) opsin gene covering amino acid positions 86, 90, and 93 and has been utilized in a wide range of avian species. Other key tuning sites have been proposed but not sequenced in the genomic DNA-based spectral sensitivity studies. We have designed 5 new primers for sequencing gene fragments of the ultraviolet-/violet-tuned SWS1 opsin gene containing the first, second and third, and sixth and seventh α-helical transmembrane regions and the spectral tuning sites 49, 86, 90, 93, 116, 118 and 298. Testing these primers on various bird species reveals some novel combinations of amino acid residues at the tuning sites. The potential significance of these on spectral tuning is discussed.

  • 13022.
    Ödeen, Anders
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Evolution, Animal Ecology.
    Håstad, Olle
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Evolutionary Organism Biology.
    Pollinating birds differ in spectral sensitivity2010In: Journal of Comparative Physiology A. Sensory, neural, and behavioral physiology, ISSN 0340-7594, E-ISSN 1432-1351, Vol. 196, no 2, p. 91-96Article in journal (Refereed)
    Abstract [en]

    Pollinating animals and their angiosperm hosts often show strong co-adaptation in traits that increase the likelihood of a successful transfer of pollen and nutrient rewards. One such adaptation is the reported colour difference caused by unequal distribution of anthocyanidin pigments amongst plant species visited by hummingbirds and passerines. This phenomenon has been suggested to reflect possible differences in the colour vision of these pollinating birds. The presence of any such difference in colour vision would arguably affect the ecological and evolutionary interactions between flowers and their visitors, accentuating differences in floral displays and attractiveness of plants to the favoured avian pollinators. We have tested for differences in colour vision, as indicated by the amino acid present at certain key positions in the short-wavelength-sensitive type 1 (SWS1) visual pigment opsin, between the major groups of pollinating birds: the non-passerine Trochilidae (hummingbirds), the passerine Meliphagidae (honeyeaters) and Nectariniidae (sunbirds) plus five other Passerida passerine families. The results reveal gross spectral sensitivity differences between hummingbirds and honeyeaters, on the one hand, and the Passerida species, on the other.

  • 13023.
    Ödeen, Anders
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Animal ecology.
    Håstad, Olle
    Department of Anatomy, Physiology and Biochemistry, Swedish University of Agricultural Sciences, S-75007 Uppsala, Sweden..
    The phylogenetic distribution of ultraviolet sensitivity in birds2013In: BMC Evolutionary Biology, ISSN 1471-2148, E-ISSN 1471-2148, Vol. 13, p. 36-Article in journal (Refereed)
    Abstract [en]

    Background: Colour vision in birds can be categorized into two classes, the ultraviolet (UVS) and violet sensitive (VS). Their phylogenetic distributions have traditionally been regarded as highly conserved. However, the complicated nature of acquiring spectral sensitivities from cone photoreceptors meant that until recently, only a few species had actually been studied. Whether birds are UVS or VS can nowadays be inferred from a wide range of species via genomic sequencing of the UV/violet SWS1 cone opsin gene. Results: We present genomic sequencing results of the SWS1 gene from 21 avian orders. Amino acid residues signifying UV sensitivity are found in the two most important spectral tuning sites 86 and 90 of Pteroclidiformes and Coraciiformes, in addition to the major clades, Palaeognathae, Charadriiformes, Trogoniformes, Psittaciformes and Passeriformes, where they where previously known to occur. We confirm that the presumed UVS-conferring amino acid combination F86, C90 and M93 is common to Palaeognathae and unique to this clade, despite available spectrometric evidence showing the ostrich retina to be VS. Conclusions: By mapping our results together with data from previous studies on a molecular phylogeny we show that avian colour vision shifted between VS and UVS at least 14 times. Single nucleotide substitutions can explain all these shifts. The common ancestor of birds most likely had a VS phenotype. However, the ancestral state of the avian SWS1 opsin's spectral tuning sites cannot be resolved, since the Palaeognathae are F86, C90 while the Neognathae are ancestrally S86, S90. The phylogenetic distribution of UVS and VS colour vision in birds is so complex that inferences of spectral sensitivities from closely related taxa should be used with caution.

  • 13024.
    Ödeen, Anders
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Evolution, Animal Ecology.
    Håstad, Olle
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Evolutionary Organism Biology.
    Alström, Per
    Department of Vertebrate Zoology, Swedish Museum of Natural History.
    Evolution of ultraviolet vision in shorebirds (Charadriiformes)2010In: Biology Letters, ISSN 1744-9561, E-ISSN 1744-957X, Vol. 6, no 3, p. 370-374Article in journal (Refereed)
    Abstract [en]

    Diurnal birds belong to one of two classes of colour vision. These are distinguished by the maximum absorbance wavelengths of the SWS1 visual pigment sensitive to violet (VS) and ultraviolet (UVS). Shifts between the classes have been rare events during avian evolution. Gulls (Laridae) are the only shorebirds (Charadriiformes) previously reported to have the UVS type of opsin, but too few species have been sampled to infer that gulls are unique among shorebirds or that Laridae is monomorphic for this trait. We have sequenced the SWS1 opsin gene in a broader sample of species. We confirm that cysteine in the key amino acid position 90, characteristic of the UVS class, has been conserved throughout gull evolution but also that the terns Anous minutus, A. tenuirostris and Gygis alba, and the skimmer Rynchops niger carry this trait. Terns, excluding Anous and Gygis, share the VS conferring serine in position 90 with other shorebirds but it is translated from a codon more similar to that found in UVS shorebirds. The most parsimonious interpretation of these findings, based on a molecular gene tree, is a single VS to UVS shift and a subsequent reversal in one lineage.

  • 13025.
    Ödeen, Anders
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Animal Ecology.
    Håstad, Olle
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology.
    Alström, Per
    Evolution of ultraviolet vision in the largest avian radiation: the passerines2011In: BMC Evolutionary Biology, ISSN 1471-2148, E-ISSN 1471-2148, Vol. 11, p. 313-Article in journal (Refereed)
    Abstract [en]

    Background: Interspecific variation in avian colour vision falls into two discrete classes: violet sensitive (VS) and ultraviolet sensitive (UVS). They are characterised by the spectral sensitivity of the most shortwave sensitive of the four single cones, the SWS1, which is seemingly under direct control of as little as one amino acid substitution in the cone opsin protein. Changes in spectral sensitivity of the SWS1 are ecologically important, as they affect the abilities of birds to accurately assess potential mates, find food and minimise visibility of social signals to predators. Still, available data have indicated that shifts between classes are rare, with only four to five independent acquisitions of UV sensitivity in avian evolution. Results: We have classified a large sample of passeriform species as VS or UVS from genomic DNA and mapped the evolution of this character on a passerine phylogeny inferred from published molecular sequence data. Sequencing a small gene fragment has allowed us to trace the trait changing from one stable state to another through the radiation of the passeriform birds. Their ancestor is hypothesised to be UVS. In the subsequent radiation, colour vision changed between UVS and VS at least eight times. Conclusions: The phylogenetic distribution of SWS1 cone opsin types in Passeriformes reveals a much higher degree of complexity in avian colour vision evolution than what was previously indicated from the limited data available. Clades with variation in the colour vision system are nested among clades with a seemingly stable VS or UVS state, providing a rare opportunity to understand how an ecologically important trait under simple genetic control may co-evolve with, and be stabilised by, associated traits in a character complex.

  • 13026.
    Ödeen, Anders
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Evolution, Animal Ecology.
    Moray, Clea M.
    Drosophila melanogaster virgins are more likely to mate with strangers than familiar flies2008In: Die Naturwissenschaften, ISSN 0028-1042, E-ISSN 1432-1904, Vol. 95, no 3, p. 253-256Article in journal (Refereed)
    Abstract [en]

    Recent evidence shows that females of many species can discriminate against males and/or male phenotypes they have mated with previously. However, these studies have not tested whether actual mating is necessary to induce the avoidance behaviour. A preference for strangers may have evolved because it avoids multiple matings with similar genotypes. Alternatively, there may be selection against mating with familiar individuals directly. By choosing its first mate among unfamiliar individuals (which are less likely close relatives than are those encountered early in life), a virgin might disentangle some of the potential benefits of avoiding genetic incompatibility and inbreeding in the offspring from the costs of remating. In this study, we test whether Drosophila melanogaster flies bias their mate choice towards strangers according to previous, non-copulatory, experience. Based on 173 trials over 12 weeks, virgin females presented with two virgin males were 59% more likely to mate with a novel male than the one which she had been housed with for 8 h the day before. Hence we present the first report showing that a dipteran can distinguish between previously encountered and not previously encountered conspecifics.

  • 13027.
    Ödeen, Anders
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Animal Ecology.
    Pruett-Jones, Stephen
    Driskell, Amy C.
    Armenta, Jessica K.
    Håstad, Olle
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Evolution and Developmental Biology.
    Multiple shifts between violet and ultraviolet vision in a family of passerine birds with associated changes in plumage coloration2012In: Proceedings of the Royal Society of London. Biological Sciences, ISSN 0962-8452, E-ISSN 1471-2954, Vol. 279, no 1732, p. 1269-1276Article in journal (Refereed)
    Abstract [en]

    Colour vision in diurnal birds falls into two discrete classes, signified by the spectral sensitivity of the violet- (VS) or ultraviolet-sensitive (UVS) short wavelength-sensitive type 1 (SWS1) single cone. Shifts between sensitivity classes are rare; three or four are believed to have happened in the course of avian evolution, one forming UVS higher passerines. Such shifts probably affect the expression of shortwave-dominated plumage signals. We have used genomic DNA sequencing to determine VS or UVS affinity in fairy-wrens and allies, Maluridae, a large passerine family basal to the known UVS taxa. We have also spectrophotometrically analysed male plumage coloration as perceived by the VS and UVS vision systems. Contrary to any other investigated avian genus, Malurus (fairy-wrens) contains species with amino acid residues typical of either VS or UVS cone opsins. Three bowerbird species (Ptilonorhynchidae) sequenced for outgroup comparison carry VS opsin genes. Phylogenetic reconstructions render one UVS gain followed by one or more losses as the most plausible evolutionary scenario. The evolution of avian ultraviolet sensitivity is hence more complex, as a single shift no longer explains its distribution in Passeriformes. Character correlation analysis proposes that UVS vision is associated with shortwave-reflecting plumage, which is widespread in Maluridae.

  • 13028. Öhman, Johan
    et al.
    Jakobsson, Emma
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Källström, Ulla
    Elmblad, Annette
    Ansari, Akbar
    Kalderen, Christina
    Robertson, Elinor
    Danielsson, Eva
    Gustavsson, Anna-Lena
    Varadi, Andrea
    Ekblom, Jonas
    Holmgren, Erik
    Doverskog, Magnus
    Abrahamsen, Lars
    Nilsson, Joakim
    Production of a truncated soluble human semicarbazide-sensitive amine oxidase (SSAO) mediated by a GST-fusion protein secreted from HEK293 cellsArticle in journal (Refereed)
  • 13029.
    Öhman, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Biology Education Centre.
    Betingad immunpåverkan och medicinskdosreduktion: en kritisk granskning av tillämpad placebo2014Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
    Abstract [sv]

    Placeboeffekten; att få klinisk effekt av inaktiv behandling är ett fenomen som tilldrar sig allt större intresse. Trots att mekanismerna bakom effekten ännu är långt ifrån helt klarlagda så finns en stor mängd forskning som visar att placebobehandling på olika vis kan vara av klinisk relevans. Bland de mest imponerande demonstrationerna av placeboeffekten är de experiment som visar att s.k. klassisk betingning kan påverka immunförsvaret. Experiment har visat att detta är möjligt både hos gnagare och människor: en medicin administreras samtidigt som ett neutralt gustatoriskt stimulus i vad som kallas betingningsfasen. När denna genomförts kan associationen mellan smak och farmakologisk effekt vara så stark att samma smak, på egen hand, kan framkalla nämnd effekt. I detta arbete sammanfattas kort begrepp och forskning kring placebo i allmänhet och betingad placebo i synnerhet. Vetenskapliga belägg för betingad placebos förmåga till immunpåverkan granskas, och det mesta tyder på att sådan är möjlig i praktiken. Därefter diskuteras möjliga kliniska tillämpningar av betingad placebo i form av medicinsk dosreduktion. Avslutningsvis följer en kort genomgång av det stora kunskapsgapet mellan beläggen för denna dosreduktions kliniska relevans, och dess lämplighet inom konventionell vård.

  • 13030.
    Öhrngren, Per
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Wu, Xiongyu
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Persson, Magnus
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Structure and Molecular Biology.
    Ekegren, Jenny
    Wallberg, Hans
    Vrang, Lotta
    Rosenquist, Åsa
    Samuelsson, Bertil
    Unge, Torsten
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Structure and Molecular Biology.
    Larhed, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Hiv-1 Protease Inhibitors with a Tertiary Alcohol Containing a Transition-State Mimic and Various P2/P1´ Substituents2011In: MedChemComm, ISSN 2040-2503, E-ISSN 2040-2511, Vol. 2, no 8, p. 701-709Article in journal (Refereed)
    Abstract [en]

    Two series, including in total 18 novel HIV-1 protease inhibitors, comprising a tertiary alcohol as thetransition-state mimic have been synthesised and evaluated. Replacement of the previously used, butmetabolically unstable, indanol amide group with amino acid derived aliphatic P2–P3 moietiesprovided potent inhibitors with low Ki- and EC50-values (2.7 nM and 2.0 mM, respectively). The P10subunit was varied using 10 different aromatic and heteroaromatic substituents furnishing thecorresponding inhibitors with retained activity. Permeability and stability studies showed examples inthe same range as Atazanavir. X-Ray crystallographic analysis of two selected inhibitor enzyme cocomplexes(9a and 9d) supplied detailed structural information. The binding modes were compared tothose of Atazanavir and a previously reported indanol amide containing inhibitor (14). The novelinhibitors with an elongated P1' side chain enabled a previously unexploited edge-on interaction withPhe53/153. Exchange of the previously used indanol amide P2 moiety, with a tert-leucine derived P2–P3side chain, furnished small main chain displacements in the S2–S3 pocket. The methyl amide in the P3 position caused a 2 Å shift of the Arg8/108 in comparison to 14, indicating the flexibility of the proteaseactive site.

  • 13031.
    Öquist, Mats G.
    et al.
    Department of Forest Ecology and Management, Swedish University of Agricultural Sciences (SLU).
    Bishop, Kevin
    Uppsala University, Disciplinary Domain of Science and Technology, Earth Sciences, Department of Earth Sciences, LUVAL. Uppsala University, Disciplinary Domain of Science and Technology, Earth Sciences, Department of Earth Sciences, Uppsala Centre for Sustainable Development, CSD Uppsala.
    Grelle, Achim
    Department of Ecology, Swedish University of Agricultural Sciences (SLU).
    Klemedtsson, Leif
    Department of Earth Sciences, Gothenburg University.
    Köhler, Stephan J.
    Department of Aquatic Sciences and Assessment, Swedish University of Agricultural Sciences (SLU).
    Laudon, Hjalmar
    Department of Forest Ecology and Management, Swedish University of Agricultural Sciences (SLU).
    Lindroth, Anders
    Department of Physical Geography and Ecosystem Analysis, Lund University.
    Ottosson Löfvenius, Mikaell
    Department of Forest Ecology and Management, Swedish University of Agricultural Sciences (SLU).
    Wallin, Marcus B.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Limnology.
    Nilsson, Mats B.
    Department of Forest Ecology and Management, Swedish University of Agricultural Sciences (SLU).
    The full annual carbon balance of boreal forestsis highly sensitive to precipitation2014In: Environmental Science and Technology Letters, ISSN 2328-8930, Vol. 1, no 7, p. 315-319Article in journal (Refereed)
    Abstract [en]

    The boreal forest carbon balance is predicted to be particularly sensitive to climate change. Carbon balance estimates of these biomes stem mainly from eddy-covariance measurements of net ecosystem exchange (NEE). However, a full net ecosystem carbon balance (NECB) must include the lateral carbon export (LCE) through discharge. We show that annual LCE at a boreal forest site ranged from 4 to 28%, averaging 11% (standard deviation of 8%), of annual NEE over 13 years. Annual LCE and NEE are strongly anticorrelated; years with weak NEE coincide with high LCE. The decreased NEE in response to increased precipitation is caused by a reduction in the amount of incoming radiation caused by clouds. If our finding is also valid for other sites, it implies that increased precipitation at high latitudes may shift forest NECB in large areas of the boreal biome. Our results call for future analysis of this dual effect of precipitation on NEE and LCE.

  • 13032.
    Örberg, Jan
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Behaviour2007In: Reproductive Toxicology in Environmental Research: a report from the ReproSafe-programme, ISSN 0282-7298, Vol. Report 5729Article, review/survey (Other (popular scientific, debate etc.))
  • 13033.
    Örlén, Hanna
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Hughes, Diarmaid
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Weak mutators can drive the evolution of fluoroquinolone resistance in Escherichia coli2006In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 50, no 10, p. 3454-3456Article in journal (Refereed)
    Abstract [en]

    Weak mutators are common among clinical isolates of Escherichia coli. We show that the relative mutation rate and the "evolvability of fluoroquinolone resistance" are related by a power law slope of 1.2 over 3 orders of magnitude. Thus, even weak mutators can drive the evolution of fluoroquinolone resistance under selection pressure.

  • 13034.
    Östberg, Linus J.
    et al.
    Karolinska Inst, Sci Life Lab, Dept Med Biochem & Biophys, Stockholm, Sweden..
    Persson, Bengt
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics. Karolinska Inst, Sci Life Lab, Dept Med Biochem & Biophys, Stockholm, Sweden..
    Höög, Jan-Olov
    Karolinska Inst, Dept Med Biochem & Biophys, Stockholm, Sweden..
    Computational studies of human class V alcohol dehydrogenase - the odd sibling2016In: BMC Biochemistry, ISSN 1471-2091, E-ISSN 1471-2091, Vol. 17, article id 16Article in journal (Refereed)
    Abstract [en]

    Background: All known attempts to isolate and characterize mammalian class V alcohol dehydrogenase (class V ADH), a member of the large ADH protein family, at the protein level have failed. This indicates that the class V ADH protein is not stable in a non-cellular environment, which is in contrast to all other human ADH enzymes. In this report we present evidence, supported with results from computational analyses performed in combination with earlier in vitro studies, why this ADH behaves in an atypical way. Results: Using a combination of structural calculations and sequence analyses, we were able to identify local structural differences between human class V ADH and other human ADHs, including an elongated beta-strands and a labile a-helix at the subunit interface region of each chain that probably disturb it. Several amino acid residues are strictly conserved in class I-IV, but altered in class V ADH. This includes a for class V ADH unique and conserved Lys51, a position directly involved in the catalytic mechanism in other ADHs, and nine other class V ADH-specific residues. Conclusions: In this study we show that there are pronounced structural changes in class V ADH as compared to other ADH enzymes. Furthermore, there is an evolutionary pressure among the mammalian class V ADHs, which for most proteins indicate that they fulfill a physiological function. We assume that class V ADH is expressed, but unable to form active dimers in a non-cellular environment, and is an atypical mammalian ADH. This is compatible with previous experimental characterization and present structural modelling. It can be considered the odd sibling of the ADH protein family and so far seems to be a pseudoenzyme with another hitherto unknown physiological function.

  • 13035.
    Östby, David
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Biology Education Centre.
    Tvättbjörnen (Procyon lotor) som invasiv art i Europa2014Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
    Abstract [sv]

    Invasiva arter är organismer som med människans hjälp spridit sig till nya områden och sedan sprider sig bortom all kontroll på bekostnad av sitt nya habitat, ekosystem eller andra arter. Detta är ett globalt problem, och kan få konsekvenser både i ekonomiska, sociala och ekologiska aspekter. Människan har ända sedan antiken fört in främmande arter i Europa, men problemet har ökat på senare år. En av de värsta invasiva arter vi har idag är tvättbjörnen, vilken normalt sätt hör hemma i Nordamerika. Den tillhör familjen halvbjörnar och utmärker sig genom sina fingerfärdiga framtassar, sin nyfikenhet och goda anpassningsförmåga. Till Europa har den kommit genom att ha rymt samt släppts ut från pälsfarmer och djurparker. Populationen är som störst i Tyskland, framförallt i städerna, och den sprider sig nu genom Europa i en alarmerande takt. Man fruktar att den kan bära på sjukdomar och parasiter samt hota delar av Europas ekosystem. Dessutom kan arten komma att ställa till med ekonomiska problem i byggnader och på odlingar på samma sätt som i Japan där den också introducerats. I Tyskland har man länge bedrivit jakt på arten, men det tycks inte stoppa tvättbjörnen då den ändå har ökat exponentiellt i antal. Det enda som verkar kunna sätta stopp för artens expansion i Europa är geografiska barriärer som till exempel hav, samt kalla vintrar eftersom tvättbjörnen begränsas av hur mycket energireserver den kan bygga upp under hösten för att klara övervintringen. I och med människans aktiviteter och klimatförändringarna är det dock möjligt för tvättbjörnen att övervinna även dessa hinder. Det ser ut som att större delen av Europa kommer tvingas att acceptera tvättbjörnen som en naturlig del av faunan, och det är därför viktigt att bedriva mer forskning kring dess ekologi i Europa för att kunna anpassa samhället och naturvården för att minimera dess negativa påverkan.

  • 13036.
    Österberg, Fredrik
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Structural Molecular Biology.
    Exploring Ligand Binding in HIV-1 Protease and K+ Channels Using Computational Methods2005Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Understanding protein-ligand interactions is highly important in drug development. In the present work the objective is to comprehend the link between structure and function using molecular modelling. Specifically, this thesis has been focused on implementation of receptor flexibility in molecular docking and studying structure-activity relationships of potassium ion channels and their blockers.

    In ligand docking simulations protein motion and heterogeneity of structural waters are approximated using an ensemble of protein structures. Four methods of combining multiple target structures within a single grid-based lookup table of interaction energies are tested. Two weighted average methods permit consistent and accurate ligand docking using a single grid representation of the target protein structures.

    Quaternary ammonium ions (QAIs) are well known K+ channel blockers. Conformations around C–N bonds at the quaternary centre in tetraalkylammonium ions in water solution are investigated using quantum mechanical methods. Relative solvation free energies of QAIs are further estimated from molecular dynamics simulations. The torsion barrier for a two-step interconversion between the conformations D2d and S4 is calculated to be 9.5 kcal mol–1. Furthermore D2d is found to be more stable than the S4 conformation which is in agreement with experimental studies. External QAI binding to the K+ channel KcsA is also studied. Computer simulations and relative binding free energies of the KcsA complexes with QAIs are calculated. This is done with the molecular dynamics free energy perturbation approach together with automated ligand docking. In agreement with experiment, the Et4N+ blocker in D2d symmetry has better binding than the other QAIs.

    Binding of blockers to the human cardiac hERG potassium channel is studied using a combination of homology modelling, automated docking and molecular dynamics simulations. The calculations reproduce the relative binding affinities of a set of drug derivatives very well and indicate that both polar interactions near the intracellular opening of the selectivity filter as well as hydrophobic complementarity in the region around F656 are important for blocker binding. Hence, the derived model of hERG should be useful for further interpretations of structure-activity relationships.

    List of papers
    1. Automated docking to multiple target structures: Incorporation of protein mobility and structural water heterogeneity in AutoDock
    Open this publication in new window or tab >>Automated docking to multiple target structures: Incorporation of protein mobility and structural water heterogeneity in AutoDock
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    2002 (English)In: Proteins: Structure, Function, and Genetics, Vol. 46, no 1, p. 7-Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-93805 (URN)
    Available from: 2005-11-11 Created: 2005-11-11 Last updated: 2009-06-02Bibliographically approved
    2. Computational and NMR study of quaternary ammonium ion conformations in solution
    Open this publication in new window or tab >>Computational and NMR study of quaternary ammonium ion conformations in solution
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    2002 (English)In: Physical Chemistry Chemical Physics, Vol. 4, no 19, p. 4640-4647Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-93806 (URN)10.1039/b203526j (DOI)
    Available from: 2005-11-11 Created: 2005-11-11 Last updated: 2009-06-02Bibliographically approved
    3. Structure-activity relationship for extracellular block of K+ channels by tetraalkylammonium ions
    Open this publication in new window or tab >>Structure-activity relationship for extracellular block of K+ channels by tetraalkylammonium ions
    2003 (English)In: FEBS Letter, Vol. 554, no 1-2, p. 6-Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-93807 (URN)
    Available from: 2005-11-11 Created: 2005-11-11 Last updated: 2009-06-02Bibliographically approved
    4. Exploring blocker binding to a homology model of the open hERG K+ channel using docking and molecular dynamics methods
    Open this publication in new window or tab >>Exploring blocker binding to a homology model of the open hERG K+ channel using docking and molecular dynamics methods
    2005 (English)In: FEBS Letter, Vol. 579, no 13, p. 2939-44Article in journal (Refereed) Published
    Keywords
    Amino Acid Sequence, Ether-A-Go-Go Potassium Channels, Humans, Models; Molecular, Molecular Sequence Data, Potassium Channels; Voltage-Gated/antagonists & inhibitors/chemistry/*metabolism, Research Support; Non-U.S. Gov't, Sequence Homology; Amino Acid
    Identifiers
    urn:nbn:se:uu:diva-93808 (URN)10.1002/prot.10028 (DOI)15893317 (PubMedID)
    Available from: 2005-11-11 Created: 2005-11-11 Last updated: 2009-06-02Bibliographically approved
  • 13037.
    Österberg, Fredrik
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Structural Molecular Biology.
    Morris, Garrett
    Sanner, Michel
    Olson, Arthur
    Goodsell, David
    Automated docking to multiple target structures: Incorporation of protein mobility and structural water heterogeneity in AutoDock2002In: Proteins: Structure, Function, and Genetics, Vol. 46, no 1, p. 7-Article in journal (Refereed)
  • 13038.
    Österberg, Fredrik
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Structural Molecular Biology.
    Åqvist, Johan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Structural Molecular Biology.
    Exploring blocker binding to a homology model of the open hERG K+ channel using docking and molecular dynamics methods2005In: FEBS Letter, Vol. 579, no 13, p. 2939-44Article in journal (Refereed)
  • 13039.
    Östergren, Tiolina
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Biology Education Centre.
    Identification of MYCN and SOX9 target genes and a study of drug treatment effects in medulloblastoma2015Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    Medulloblastoma (MB) is the most common malignant brain tumor affecting children. The transcription factors MYCN and SOX9 are associated with initiation, maintenance and recurrence of MB and are also connected to more aggressive tumors. In this study, a ChIP was performed to isolate DNA from genes that are transcriptionally regulated by these proteins. Identification of these target genes will reveal new potential drug targets and help us better understand the functions of MYCN and SOX9. The ChIP was not fully optimized during this project and the target genes were not sent for sequencing and identified. To study the connection between SOX9 and recurrence, cells with different levels of SOX9 were treated with drugs, after which cell viability was measured. No significant difference in resistance could be measured. Change in expression level of MYCN, SOX9 and other relevant genes after drug treatment was also studied. The results show an increase in SOX9 and HES1, suggesting that these genes are involved in tumor recurrence.

  • 13040.
    Östlin, Christofer
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Biology Education Centre.
    Single-molecule X-ray free-electron laser imaging: Interconnecting sample orientation with explosion data2014Independent thesis Advanced level (professional degree), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    X-ray crystallography has been around for 100 years and remains the preferred technique for solving molecular structures today. However, its reliance on the production of sufficiently large crystals is limiting, considering that crystallization cannot be achieved for a vast range of biomolecules. A promising way of circumventing this problem is the method of serial femtosecond imaging of single-molecules or nanocrystals utilizing an X-ray free-electron laser.

    In such an approach, X-ray pulses brief enough to outrun radiation damage and intense enough to provide usable diffraction signals are employed. This way accurate snapshots can be collected one at a time, despite the sample molecule exploding immediately following the pulse due to extreme ionization. But as opposed to in conventional crystallography, the spatial orientation of the molecule at the time of X-ray exposure is generally unknown. Consequentially, assembling the snapshots to form a three-dimensional representation of the structure of interest is cumbersome, and normally tackled using algorithms to analyze the diffraction patterns.

    Here we explore the idea that the explosion data can provide useful insights regarding the orientation of ubiquitin, a eukaryotic regulatory protein. Through two series of molecular dynamics simulations totaling 588 unique explosions, we found that a majority of the carbon atoms prevalent in ubiquitin are directionally limited in their respective escape paths. As such we conclude it to be theoretically possible to orient a sample with known structure based on its explosion pattern. Working with an unknown sample, we suggest these discoveries could be applicable in tandem with X-ray diffraction data to optimize image assembly.

  • 13041.
    Östlin, Christofer
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Molecular and Condensed Matter Physics.
    Timneanu, Nicusor
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Molecular and Condensed Matter Physics. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular biophysics.
    Jönsson, H. Olof
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Molecular and Condensed Matter Physics.
    Ekeberg, Tomas
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular biophysics.
    Martin, Andrew V.
    University of Melbourne, School of Physics, ARC Centre of Excellence for Advanced Molecular Imaging.
    Caleman, Carl
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Molecular and Condensed Matter Physics. Center for Free-Electron Laser Science, DESY, Notkestraße 85, DE-22607 Hamburg, Germany .
    Reproducibility of Single Protein Explosions Induced by X-ray Lasers2018In: Physical Chemistry, Chemical Physics - PCCP, ISSN 1463-9076, E-ISSN 1463-9084, Vol. 20, no 18, p. 12381-12389Article in journal (Refereed)
    Abstract [en]

    Single particle imaging (SPI) using X-ray pulses has become increasingly attainable with the advent of high-intensity free electron lasers. Eliminating the need for crystallized samples enables structural studies of molecules previously inaccessible by conventional crystallography. While this emerging technique already demonstrates substantial promise, some obstacles need to be overcome before SPI can reach its full potential. One such problem is determining the spatial orientation of the sample at the time of X-ray interaction. Existing solutions rely on diffraction data and are computationally demanding and sensitive to noise. In this in silico study, we explore the possibility of aiding these methods by mapping the ion distribution as the sample undergoes a Coulomb explosion following the intense ionization. By detecting the ions ejected from the fragmented sample, the orientation of the original sample should be possible to determine. Knowledge of the orientation has been shown earlier to be of substantial advantage in the reconstruction of the original structure. 150 explosions of each of twelve separate systems – four polypeptides with different amounts of surface bound water – were simulated with molecular dynamics (MD) and the average angular distribution of carbon and sulfur ions was investigated independently. The results show that the explosion maps are reproducible in both cases, supporting the idea that orientation information is preserved. Additional water seems to restrict the carbon ion trajectories further through a shielding mechanism, making the maps more distinct. For sulfurs, water has no significant impact on the trajectories, likely due to their higher mass and greater ionization cross section, indicating that they could be of particular interest. Based on these findings, we conclude that explosion data can aid spatial orientation in SPI experiments and could substantially improve the capabilities of the novel technique.

  • 13042.
    Östlund, Andreas
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Biology Education Centre.
    Andersson, Christoffer
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Biology Education Centre.
    Öman, Daniel
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Biology Education Centre.
    Perman, Ebba
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Biology Education Centre.
    Eriksson, Hanna
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Biology Education Centre.
    Lindström, John
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Biology Education Centre.
    Possnert, Oliver
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Biology Education Centre.
    Strategier för minskad glykosylering vid proteinproduktion i Pichia pastoris: Förbättrad kvalitet på rekombinanta allergener2016Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
  • 13043.
    Östlund, C
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Centre for Image Analysis. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Evolution, Limnology. Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computerized Image Analysis.
    Flink, P
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Evolution. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Evolution, Limnology.
    Strömbeck, N
    Pierson, D
    Lindell, T
    Mapping of the water quality of Lake Erken, Sweden, from Imaging Spectrometry and Landsat Thematic Mapper2001In: Science of the Total Environment, ISSN 0048-9697, E-ISSN 1879-1026, Vol. 268, no 1-3, p. 139-154Article in journal (Refereed)
    Abstract [en]

    Hyperspectral data have been collected by the Compact Airborne Spectrographic Imager (CASI) and multispectral data by the Landsat Thematic Mapper (TM) instrument for the purpose of mapping lake water quality. Field campaigns have been performed on Lake Erken

  • 13044.
    Östlund-Nilsson, Sara
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Evolutionary Biology.
    Female choice and paternal care in the fifteen-spined stickleback, Spinachia spinachia2000Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    In the fifteen-spined stickleback, Spinachia spinachia, males provide females with direct benefits by fanning, cleaning and guarding the offspring. Males announce their parental skills through intense body shakes during courtship. Females preferred to mate with more intensely shaking males. As a result, females got better fathers for their offspring, as such males achieved a higher hatching success. Not only did male behavioural cues attract females, but males also used their nests as extrabodily ornaments. The nest is held together with shiny secretional threads consisting of a glycoprotein. Females chose to spawn in nests with more secretional threads. A likely reason for this is that the threads are metabolically costly for the male to produce and the amount of secretion indicates a male's nutritional status, which is of great importance as parental duties are energetically costly. Moreover, females preferred nests built high up in the vegetation, as such nests were safer from egg predators. Competition with other males for females favoured males building higher nests than did their neighbours, probably because females preferred high nests. Male-male interactions, such as sneaking and egg stealing, caused decreased paternity among males in nature as assessed by a microsatellite analysis. Males adjusted their paternal effort according to their previous investment in the brood, but not according to paternity. Thus, female choice is based on multiple cues and results in better paternal care. Males invest in courtship, male-male competition, nest construction and paternal care, the outcome determining their success in mate attraction.

  • 13045.
    Östman, Carina
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Evolution and Developmental Biology.
    Edwardsiella carnea (Gosse, 1856) (Cnidaria, Actiniaria, Edwardsiidae), the presumed adult sea anemone to