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  • 1.
    Bassan, Arianna
    Stockholm University, Faculty of Science, Department of Physics.
    Theoretical studies of mononuclear non-heme iron active sites2004Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The quantum chemical investigations presented in this thesis use hybrid density functional theory to shed light on the catalytic mechanisms of mononuclear non-heme iron oxygenases, accommodating a ferrous ion in their active sites. More specifically, the dioxygen activation process and the subsequent oxidative reactions in the following enzymes were studied: tetrahydrobiopterin-dependent hydroxylases, naphthalene 1,2-dioxygenase and α-ketoglutarate-dependent enzymes. In light of many experimental efforts devoted to the functional mimics of non-heme iron oxygenases, the reactivity of functional analogues was also examined.

    The computed energetics and the available experimental data served to assess the feasibility of the reaction mechanisms investigated. Dioxygen activation in tetrahydrobiopterin- and α-ketoglutarate-dependent enzymes were found to involve a high-valent iron-oxo species, which was then capable of substrate hydroxylation. In the case of naphthalene 1,2-dioxygenase, the reactivity of an iron(III)-hydroxperoxo species toward the substrate was investigated and compared to the biomimetic counterpart.

  • 2.
    Bjelkmar, Pär
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Modeling of voltage-gated ion channels2011Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The recent determination of several crystal structures of voltage-gated ion channels has catalyzed computational efforts of studying these remarkable molecular machines that are able to conduct ions across biological membranes at extremely high rates without compromising the ion selectivity.

    Starting from the open crystal structures, we have studied the gating mechanism of these channels by molecular modeling techniques. Firstly, by applying a membrane potential, initial stages of the closing of the channel were captured, manifested in a secondary-structure change in the voltage-sensor. In a follow-up study, we found that the energetic cost of translocating this 310-helix conformation was significantly lower than in the original conformation. Thirdly, collaborators of ours identified new molecular constraints for different states along the gating pathway. We used those to build new protein models that were evaluated by simulations. All these results point to a gating mechanism where the S4 helix undergoes a secondary structure transformation during gating.

    These simulations also provide information about how the protein interacts with the surrounding membrane. In particular, we found that lipid molecules close to the protein diffuse together with it, forming a large dynamic lipid-protein cluster. This has important consequences for the understanding of protein-membrane interactions and for the theories of lateral diffusion of membrane proteins.

    Further, simulations of the simple ion channel antiamoebin were performed where different molecular models of the channel were evaluated by calculating ion conduction rates, which were compared to experimentally measured values. One of the models had a conductance consistent with the experimental data and was proposed to represent the biological active state of the channel.

    Finally, the underlying methods for simulating molecular systems were probed by implementing the CHARMM force field into the GROMACS simulation package. The implementation was verified and specific GROMACS-features were combined with CHARMM and evaluated on long timescales. The CHARMM interaction potential was found to sample relevant protein conformations indifferently of the model of solvent used.

  • 3. Chen, Dan
    et al.
    Ranganathan, Anirudh
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Ijzerman, Adriaan P.
    Siegal, Gregg
    Carlsson, Jens
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Complementarity between in Silico and Biophysical Screening Approaches in Fragment-Based Lead Discovery against the A(2A) Adenosine Receptor2013In: Journal of Chemical Information and Modeling, ISSN 1549-9596, E-ISSN 1549-960X, Vol. 53, no 10, p. 2701-2714Article in journal (Refereed)
    Abstract [en]

    Fragment-based lead discovery (FBLD) is becoming an increasingly important method in drug development. We have explored the potential to complement NMR-based biophysical screening of chemical libraries with molecular docking in FBLD against the A(2A) adenosine receptor (A(2A)AR), a drug target for inflammation and Parkinson's disease. Prior to an NMR-based screen of a fragment library against the A(2A)AR, molecular docking against a crystal structure was used to rank the same set of molecules by their predicted affinities. Molecular docking was able to predict four out of the five orthosteric ligands discovered by NMR among the top 5% of the ranked library, suggesting that structure-based methods could be used to prioritize among primary hits from biophysical screens. In addition, three fragments that were top-ranked by molecular docking, but had not been picked up by the NMR-based method, were demonstrated to be A2AAR ligands. While biophysical approaches for fragment screening are typically limited to a few thousand compounds, the docking screen was extended to include 328,000 commercially available fragments. Twenty-two top-ranked compounds were tested in radioligand binding assays, and 14 of these were A(2A)AR ligands with K-i values ranging from 2 to 240 mu M. Optimization of fragments was guided by molecular dynamics simulations and free energy calculations. The results illuminate strengths and weaknesses of molecular docking and demonstrate that this method can serve as a valuable complementary tool to biophysical screening in FBLD.

  • 4.
    Doverstål, Mats
    Stockholm University, Faculty of Science.
    Experimental studies of dimers and clusters1994Doctoral thesis, comprehensive summary (Other academic)
  • 5.
    Eriksson, Lars
    et al.
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK).
    Grins, Jekabs
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK).
    Svensson, Gunnar
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK).
    DFT predictions of Prussian Blue structures2018In: DFT predictions of Prussian Blue structures, 2018Conference paper (Refereed)
  • 6.
    Fromager, Emmanuel
    et al.
    Stockholm University, Faculty of Science, Department of Physics.
    Teichteil, Christian
    Maron, Laurent
    Extraction of shape-consistent spin-orbit pseudopotential from an effective spin-orbit parameter and application to the tellurium atom2006In: International Journal of Quantum Chemistry, ISSN 0020-7608, E-ISSN 1097-461X, Vol. 106, no 3, p. 764-771Article in journal (Refereed)
    Abstract [en]

    A hybrid procedure to extract spin-orbit pseudo-potentials is proposed, taking information from both the orbital shape in the valence region and the atomic spin-orbit splitting. An effective atomic spin-orbit parameter is derived from a Dirac–Coulomb–Fock reference atomic calculation and is then used to extract the spin-orbit pseudo-potential. This method is tested for the ground-state configuration (5s25p4) of the tellurium atom.

  • 7. Furukawa, Masashi
    et al.
    Yamada, Taro
    Katano, Satoshi
    Kawai, Maki
    Ogasawara, Hirohito
    Nilsson, Anders
    Stockholm University, Faculty of Science, Department of Physics.
    Geometrical characterization of adenine and guanine on Cu(110) by NEXAFS, XPS, and DFT calculation2007In: Surface Science, ISSN 0039-6028, E-ISSN 1879-2758, Vol. 601, no 23, p. 5433-5440Article in journal (Refereed)
    Abstract [en]

    Adsorption of purine DNA bases (guanine and adenine) on Cu(110) was studied by X-ray photoelectron spectroscopy (XPS), near-edge X-ray absorption fine-structure spectroscopy (NEXAFS), and density-functional theory (DFT) calculation. At coverages near 0.2 monolayers, Angular-resolved NEXAFS analysis revealed that adenine adsorbates lie almost flat and that guanine adsorbates are tilted up on the surface with the purine ring parallel to the atom rows of Cu(110). Referring to the previous studies on pyrimidine DNA bases [M. Furukawa, H. Fujisawa, S. Katano, H. Ogasawara, Y. Kim, T. Komeda, A. Nilsson, M. Kawai, Surf. Sci. 532-535 (2003) 261], the isomerization of DNA bases on Cu(110) was found to play an important role in the adsorption geometry. Guanine, thymine and cytosine adsorption have an amine-type nitrogen next to a carbonyl group, which is dehydrogenated into imine nitrogen on Cu(110). These bases are bonded by the inherent portion of -NH-CO- altered by conversion into enolic form and dehydrogenation. Adenine contains no CO group and is bonded to Cu(110) by participation of the inherent amine parts, resulting in nearly flatly-lying position.

  • 8.
    Granseth, Erik
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Structure, prediction, evolution and genome wide studies of membrane proteins2007Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    α-helical membrane proteins constitute 20-30% of all proteins in a cell and are involved in many essential cellular functions. The structure is only known for a few hundred of them, which makes structural models important. The most common structural model of a membrane protein is the topology which is a two-dimensional representation of the structure.

    This thesis is focused on three different aspects of membrane protein structure: improving structural predictions of membrane proteins, improving the level of detail of structural models and the concept of dual topology.

    It is possible to improve topology models of membrane proteins by including experimental information in computer predictions. This was first performed in Escherichia coli and, by using homology, it was possible to extend the results to 225 prokaryotic organisms. The improved models covered ~80% of the membrane proteins in E. coli and ~30% of other prokaryotic organisms.

    However, the traditional topology concept is sometimes too simple for complex membrane protein structures, which create a need for more detailed structural models. We created two new machine learning methods, one that predicts more structural features of membrane proteins and one that predicts the distance to the membrane centre for the amino acids. These methods improve the level of detail of the structural models.

    The final topic of this thesis is dual topology and membrane protein evolution. We have studied a class of membrane proteins that are suggested to insert either way into the membrane, i.e. have a dual topology. These protein families might explain the frequent occurrence of internal symmetry in membrane protein structures.

  • 9.
    Huang, Congcong
    et al.
    Stanford.
    Wikfeldt, Kjartan Thor
    Stockholm University, Faculty of Science, Department of Physics.
    Tokushima, Takashi
    SPring-8.
    Nordlund, Dennis
    Stanford.
    Harada, Yoshi
    Bergmann, Uwe
    Stanford.
    Niebuhr, M.
    Stanford.
    Weiss, T.M.
    Stanford.
    Horikawa, Y.
    SPring-8.
    Leetmaa, Mikael
    Stockholm University, Faculty of Science, Department of Physics.
    Ljungberg, Mathias P.
    Stockholm University, Faculty of Science, Department of Physics.
    Takahashi, Osamu
    University of Hiroshima.
    Lentz, Annika
    Linköpings Universitet.
    Ojamäe, Lars
    Linköpings Universitet.
    Lyubartsev, Alexander P.
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK), Physical Chemistry.
    Shin, Shik
    Tokyo University.
    Pettersson, Lars G.M.
    Stockholm University, Faculty of Science, Department of Physics.
    Nilsson, Anders
    Stockholm University, Faculty of Science, Department of Physics.
    Reply to Soper "Fluctuations in water around a bimodal distribution of local hydrogen bonded structural motifs"2010In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 107, no 12, p. E45-Article in journal (Refereed)
  • 10.
    Johansson, Anna CV
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Solvation properties of proteins in membranes2009Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Knowledge about the insertion and stabilization of membrane proteins is a key step towards understanding their function and enabling membrane protein design. Transmembrane helices are normally quite hydrophobic to insert efficiently, but there are many exceptions with unfavorable polar or titratable residues. Since evolutionary conserved these amino acids are likely of paramount functional importance, e.g. the four arginines in the S4 voltage sensor helix of voltage-gated ion channels. This has lead to vivid discussion about their conformation, protonation state and cost of insertion. To address such questions, the main focus of this thesis has been membrane protein solvation in lipid bilayers, evaluated using molecular dynamics simulations methods.

    A main result is that polar and charged amino acids tend to deform the bilayer by pulling water/head-groups into the hydrophobic core to keep their hydrogen bonds paired, thus demonstrating the adaptiveness of the membrane to allow specific and quite complex solvation. In addition, this retained hydration suggests that the solvation cost is mainly due to entropy, not enthalpy loss. To further quantify solvation properties, free energy profiles were calculated for all amino acids in pure bilayers, with shapes correlating well with experimental in vivo values but with higher magnitudes. Additional profiles were calculated for different protonation states of the titratable amino acids, varying lipid composition and with transmembrane helices present in the bilayer. While the two first both influence solvation properties, the latter seems to be a critical aspect. When the protein fraction in the models resemble biological membranes, the solvation cost drops significantly - even to values compatible with experiment.

    In conclusion, by using simulation based methods I have been able to provide atomic scale explanations to experimental results, and in particular present a hypothesis for how the solvation of charged groups occurs.

  • 11.
    Johansson, Erik M. J.
    et al.
    Uppsala universitet.
    Odelius, Michael
    Stockholm University, Faculty of Science, Department of Physics.
    Plogmaker, Stefan
    Uppsala universitet.
    Gorgoi, Mihaela
    Helmholtz Zentrum Berlin, BESSY II.
    Svensson, Svante
    Uppsala universitet.
    Siegbahn, Hans
    Uppsala universitet.
    Rensmo, Håkan
    Uppsala universitet.
    Spin-Orbit Coupling and Metal-Ligand Interactions in Fe(II), Ru(II), and Os(II) Complexes2010In: The Journal of Physical Chemistry C, ISSN 1932-7447, E-ISSN 1932-7455, Vol. 114, no 22, p. 10314-10322Article in journal (Refereed)
    Abstract [en]

    The purpose of the present paper is to experimentally map the energy levels governing the trends observed in oxidation potentials and absorption spectra of M(bpy)32+ complexes (bpy = 2,2′-bipyridine, M = Fe(II), Ru(II), and Os(II)). Molecular films of the transition metal complexes were investigated with element specific methods using photoelectron spectroscopy (PES) at high kinetic energy using hard X-rays and by X-ray absorption spectroscopy (XAS). The results were compared to electronic structure calculations on the complexes and the ligand. The approach allows us to experimentally measure and interpret the energy levels in terms of spin−orbit coupling and metal−ligand interactions. Specifically, it was verified that the anomaly in the trend in oxidation potentials could be explained by a large spin−orbit coupling for the Os(bpy)32+. The influence of the different metal ions on the state formed upon light absorption was also investigated by N 1s X-ray absorption, and from the spectra we could determine the relative position of the levels originating from d−σ and π contributions. The results for the occupied and unoccupied electronic levels explain the lower energy of the MLCT transition of the Os(bpy)32+ in comparison to the Ru(bpy)32+.

  • 12. Karlsen, Elly Johanne
    Quantum chemical studies of catalytic N₂O decomposition and NOx storage on metal oxides2003Doctoral thesis, comprehensive summary (Other academic)
  • 13.
    Larsson, Per
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Prediction, modeling, and refinement of protein structure2010Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Accurate predictions of protein structure are important for understanding many processes in cells. The interactions that govern protein folding and structure are complex, and still far from completely understood. However, progress is being made in many areas. Here, efforts to improve the overall quality of protein structure models are described. From a pure evolutionary perspective, in which proteins are viewed in the light of gradually accumulated mutations on the sequence level, it is shown how information from multiple sources helps to create more accurate models. A very simple but surprisingly accurate method for assigning confidence measures for protein structures is also tested. In contrast to models based on evolution, physics based methods view protein structures as the result of physical interactions between atoms. Newly implemented methods are described that both increase the time-scales accessible for molecular dynamics simulations almost 10-fold, and that to some extent might be able to refine protein structures. Finally, I compare the efficiency and properties of different techniques for protein structure refinement.

  • 14.
    Liao, Rongzhen
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Quantum Chemical Cluster Modeling of Enzymatic Reactions2010Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The Quantum chemical cluster approach has been shown to be quite powerful and efficient in the modeling of enzyme active sites and reaction mechanisms. In this thesis, the reaction mechanisms of several enzymes have been investigated using the hybrid density functional B3LYP. The enzymes studied include four dinuclear zinc enzymes, namely dihydroorotase, N-acyl-homoserine lactone hydrolase, RNase Z, and human renal dipeptidase, two trinuclear zinc enzymes, namely phospholipase C and nuclease P1, two tungstoenzymes, namely formaldehyde ferredoxin oxidoreductase and acetylene hydratase, aspartate α-decarboxylase, and mycolic acid cyclopropane synthase. The potential energy profiles for various mechanistic scenarios have been calculated and analyzed. The role of the metal ions as well as important active site residues has been discussed.

      In the cluster approach, the effects of the parts of the enzyme that are not explicitly included in the model are taken into account using implicit solvation methods.

      For all six zinc-dependent enzymes studied, the di-zinc bridging hydroxide has been shown to be capable of performing nucleophilic attack on the substrate. In addition, one, two, or even all three zinc ions participate in the stabilization of the negative charge in the transition states and intermediates, thereby lowering the barriers.

      For the two tungstoenzymes, several different mechanistic scenarios have been considered to identify the energetically most feasible one. For both enzymes, new mechanisms are proposed.

      Finally, the mechanism of mycolic acid cyclopropane synthase has been shown to be a direct methyl transfer to the substrate double bond, followed by proton transfer to the bicarbonate.

      From the studies of these enzymes, we demonstrate that density functional calculations are able to solve mechanistic problems related to enzymatic reactions, and a wealth of new insight can be obtained.

  • 15.
    Light, Sara
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Investigations into the evolution of biological networks2006Doctoral thesis, monograph (Other academic)
    Abstract [en]

    Individual proteins, and small collections of proteins, have been extensively studied for at least two hundred years. Today, more than 350 genomes have been completely sequenced and the proteomes of these genomes have been at least partially mapped. The inventory of protein coding genes is the first step toward understanding the cellular machinery. Recent studies have generated a comprehensive data set for the physical interactions between the proteins of Saccharomyces cerevisiae, in addition to some less extensive proteome interaction maps of higher eukaryotes. Hence, it is now becoming feasible to investigate important questions regarding the evolution of protein-protein networks. For instance, what is the evolutionary relationship between proteins that interact, directly or indirectly? Do interacting proteins co-evolve? Are they often derived from each other? In order to perform such proteome-wide investigations, a top-down view is necessary. This is provided by network (or graph) theory.

    The proteins of the cell may be viewed as a community of individual molecules which together form a society of proteins (nodes), a network, where the proteins have various kinds of relationships (edges) to each other. There are several different types of protein networks, for instance the two networks studied here, namely metabolic networks and protein-protein interaction networks. The metabolic network is a representation of metabolism, which is defined as the sum of the reactions that take place inside the cell. These reactions often occur through the catalytic activity of enzymes, representing the nodes, connected to each other through substrate/product edges. The indirect interactions of metabolic enzymes are clearly different in nature from the direct physical interactions, which are fundamental to most biological processes, which constitute the edges in protein-protein interaction networks.

    This thesis describes three investigations into the evolution of metabolic and protein-protein interaction networks. We present a comparative study of the importance of retrograde evolution, the scenario that pathways assemble backward compared to the direction of the pathway, and patchwork evolution, where enzymes evolve from a broad to narrow substrate specificity. Shifting focus toward network topology, a suggested mechanism for the evolution of biological networks, preferential attachment, is investigated in the context of metabolism. Early in the investigation of biological networks it seemed clear that the networks often display a particular, 'scale-free', topology. This topology is characterized by many nodes with few interaction partners and a few nodes (hubs) with a large number of interaction partners. While the second paper describes the evidence for preferential attachment in metabolic networks, the final paper describes the characteristics of the hubs in the physical interaction network of S. cerevisiae.

  • 16.
    Ljungberg, Mathias P.
    et al.
    Stockholm University, Faculty of Science, Department of Physics.
    Pettersson, Lars G.M.
    Stockholm University, Faculty of Science, Department of Physics.
    Nilsson, Anders
    Stockholm University, Faculty of Science, Department of Physics.
    Vibrational interference effects in x-ray emission of a model water dimer: implications for the interpretation of the liquid spectrum2011In: Journal of Chemical Physics, ISSN 0021-9606, E-ISSN 1089-7690, Vol. 134, no 4, p. 044513-Article in journal (Refereed)
    Abstract [en]

    We apply the Kramers-Heisenberg formula to a model water dimer to discuss vibrational interference in the x-ray emission spectrum of the donor molecule for which the core-ionized potential energy surface is dissociative but bounded by the accepting molecule. A long core-hole life time leads to decay from Zundel-like, fully delocalized vibrational states in the intermediate potential without involvement of a specific dissociated component. Comparison is made to a model with an unbound intermediate state allowing dissociation to infinity which gives a sharp, fully dissociated feature and a broad molecular peak at long core-hole life time. The implications of the vibrational interference effect on the liquid water spectrum are discussed and it is proposed that this mainly gives rise to an isotope-dependent asymmetrical broadening of the lone pair peak.

  • 17.
    Lundberg, Marcus
    Stockholm University, Faculty of Science, Department of Physics.
    Challenges in Enzyme Catalysis - Photosystem II and Orotidine Decarboxylase: A Density Functional Theory Treatment2005Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Possibly the most fascinating biochemical mechanism remaining to be solved is the formation of oxygen from water in photosystem II. This is a critical part of the photosynthetic reaction that makes solar energy accessible to living organisms.

    The present thesis uses quantum chemistry, more specifically the density functional B3LYP, to investigate a mechanism where an oxyl radical bound to manganese is the active species in O-O bond formation. Benchmark calculations on manganese systems confirm that B3LYP can be expected to give accurate results. The effect of the self-interaction error is shown to be limited. Studies of synthetic manganese complexes support the idea of a radical mechanism. A manganese complex with an oxyl radical is active in oxygen formation while manganese-oxo complexes remain inactive. Formation of the O-O bond requires a spin transition but there should be no effect on the rate. Spin transitions are also required in many short-range electron-transfer reactions.

    Investigations of the superproficient enzyme orotidine decarboxylase support a mechanism that involves an invariant network of charged amino acids, acting together with at least two mobile water molecules.

  • 18.
    Melén, Karin
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Topology Prediction of Membrane Proteins: Why, How and When?2007Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Membrane proteins are of broad interest since they constitute a large fraction of the proteome in all organisms, up to 20-30%. They play a crucial role in many cellular processes mediating information flow and molecular transport across otherwise nearly impermeable membranes. Traditional three-dimensional structural analyses of membrane proteins are difficult to perform, which makes studies of other structural aspects important. The topology of an α-helical membrane protein is a two-dimensional description of how the protein is embedded in the membrane and gives valuable information on both structure and function.

    This thesis is focused on predicting the topology of α-helical membrane proteins and on assessing and improving the prediction accuracy. Reliability scores have been derived for a number of prediction methods, and have been integrated into the widely used TMHMM predictor. The reliability score makes it possible to estimate the trustworthiness of a prediction.

    Mapping the full topology of a membrane protein experimentally is time-consuming and cannot be done on a genome-wide scale. However, determination of the location of one part of a membrane protein relative to the membrane is feasible. We have analyzed the impact of incorporating such experimental information a priori into TMHMM predictions and show that the accuracy increases significantly. We further show that the C-terminal location of a membrane protein (inside or outside) is the optimal information to use as a constraint in the predictions.

    By combining experimental techniques for determining the C-terminal location of membrane proteins with topology predictions, we have produced reliable topology models for the majority of all membrane proteins in the model organisms E. coli and S. cerevisiae. The results were further expanded to ~15,000 homologous proteins in 38 fully sequenced eukaryotic genomes. This large set of reliable topology models should be useful, in particular as the structural data for eukaryotic membrane proteins is very limited.

  • 19.
    Nilsson, Anders
    et al.
    Stockholm University, Faculty of Science, Department of Physics.
    Nordlund, Dennis
    Stanford.
    Waluyo, Ira
    Stanford.
    Huang, Ningdong
    Stanford.
    Ogasawara, Hirohito
    Stanford.
    Kaya, Sarp
    Stanford.
    Bergmann, Uwe
    Stanford.
    Näslund, Lars-Åke
    Stanford.
    Öström, Henrik
    Stockholm University, Faculty of Science, Department of Physics.
    Wernet, Philippe
    Helmholtz-Zentrum Berlin, Germany.
    Andersson, Klas J.
    Haldor-Topsoe.
    Schiros, Theanne
    Stockholm University, Faculty of Science, Department of Physics.
    Pettersson, Lars G.M.
    Stockholm University, Faculty of Science, Department of Physics.
    X-ray Absorption Spectroscopy and X-ray Raman Scattering of Water : an Experimental View2010In: Journal of Electron Spectroscopy and Related Phenomena, ISSN 0368-2048, E-ISSN 1873-2526, Vol. 177, p. 99-129Article in journal (Refereed)
    Abstract [en]

    Here we present a review of X-ray absorption spectroscopy and X-ray Raman scattering with the perspective to understand the spectra of water including changes with temperature, mass of the water molecule and presence of monovalent ions. The different detection schemes are discussed and it is concluded that transmission X-ray absorption measurements, using a small area where the thickness is uniform, and X-ray Raman scattering give the most reliable spectra. Different model systems are discussed such as the surface and bulk of ice and various adsorbed monolayer structures on metal surfaces

  • 20.
    Noack, Holger
    Stockholm University, Faculty of Science, Department of Physics.
    Biomimetic Iron Complexes involved in Oxygenation and Chlorination: A Theoretical Study2010Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Biomimetic chemistry is directed towards the simulation of enzymatic reactivity with synthetic analogues. In this thesis a quantum chemical method has been employed to study the mechanism of highly reactive iron-oxo complexes involved in oxygenation and chlorination of organic substrates. The aim of this research is to gain greater understanding for the reactivity paradigm of the iron-oxo group.

    One reaction deals with the conversion of cyclohexane into adipic acid, a key chemical in industrial chemistry, catalyzed by an iron(II)-porphyrin complex in the presence of dioxygen. This process constitutes a ’green’ alternative to conventional adipic acid production, and is thus of great interest to synthetic chemistry. Another reaction investigated herein regards the selective chlorination observed for a new group of non-heme iron enzymes. With help of theoretical modeling it was possible to propose a mechanism that explains the observed selectivity. It is furthermore demonstrated how a biomimetic iron complex simulates the enzymatic reactivity by a different mechanism.

    Other topics covered in this thesis regard the structure-reactivity relationship of a binuclear iron complex and the intradiol C-C bond cleavage of catechol catalyzed by an iron(III) complex.

  • 21.
    Ohlson, Tomas
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    The use of evolutionary information in protein alignments and homology identification2006Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    For the vast majority of proteins no experimental information about the three-dimensional structure is known, but only its sequence. Therefore, the easiest way to obtain some understanding of the structure and function of these proteins is by relating them to well studied proteins. This can be done by searching for homologous proteins. It is easy to identify a homologous sequence if the sequence identity is above 30%. However, if the sequence identity drops below 30% then more sophisticated methods have to be used. These methods often use evolutionary information about the sequences, which makes it possible to identify homologous sequences with a low sequence identity.

    In order to build a three--dimensional model from the sequence based on a protein structure the two sequences have to be aligned. Here the aligned residues serve as a first approximation of the structure.

    This thesis focuses on the development of fold recognition and alignment methods based on evolutionary information. The use of evolutionary information for both query and target proteins was shown to improve both recognition and alignments. In a benchmark of profile--profile methods it was shown that the probabilistic methods were best, although the difference between several of the methods was quite small once optimal gap-penalties were used. An artificial neural network based alignment method ProfNet was shown to be at least as good as the best profile--profile method, and by adding information from a self-organising map and predicted secondary structure we were able to further improve ProfNet.

  • 22. Osipov, Vladimir Al.
    et al.
    Kowalewski, Markus
    Stockholm University, Faculty of Science, Department of Physics.
    Mukamel, Shaul
    Multiscale wavelet decomposition of time-resolved X-ray diffraction signals in cyclohexadiene2018In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 115, no 41, p. 10269-10274Article in journal (Refereed)
    Abstract [en]

    We demonstrate how the wavelet transform, which is a powerful tool for compression, filtering, and scaling analysis of signals, may be used to separate large- and short-scale electron density features in X-ray diffraction patterns. Wavelets can isolate the electron density associated with delocalized bonds from the much stronger background of highly localized core electrons. The wavelet-processed signals clearly reveal the bond formation and breaking in the early steps of the photoinduced pericyclic ring opening reaction of 1,3-cyclohexadiene, which are not resolved in the bare signal.

  • 23.
    Pelmenschikov, Vladimir
    Stockholm University, Faculty of Science, Department of Physics.
    Theoretical Modeling of Enzyme Catalysis with Focus on Radical Chemistry2005Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Hybrid density functional theory (DFT) B3LYP method is applied to study the four diverse enzyme systems: zinc-containing peptidases (thermolysin and stromelysin), methyl-coenzyme M reductase, ribonucleotide reductases (classes I and III), and superoxide dismutases (Cu,Zn- and Ni-dependent enzymes). Powerfull tools of modern quantum chemistry are used to address the questions of biological pathways at their molecular level, proposing a novel mechanism for methane production by methyl-coenzyme M reductase and providing additional insights into hydrolysis by zinc peptidases, substrate conversion by ribonucleotide reductases, and biological superoxide dismutation. Catalysis by these enzymes, with the exception of zinc peptidases, involves radical chemistry.

  • 24. Pitsevich, G. A.
    et al.
    Doroshenko, I. Yu.
    Pogorelov, V. E.
    Pettersson, Lars G. M.
    Stockholm University, Faculty of Science, Department of Physics.
    Sablinskas, V.
    Sapeshko, V. V.
    Balevicius, V.
    Combinatorial Broadening Mechanism of O-H Stretching Bands in H-Bonded Molecular Clusters2016In: Journal of Applied Spectroscopy, ISSN 0021-9037, E-ISSN 1573-8647, Vol. 83, no 3, p. 350-357Article in journal (Refereed)
    Abstract [en]

    A new mechanism for combinatorial broadening of donor-OH stretching-vibration absorption bands in molecular clusters with H-bonds is proposed. It enables the experimentally observed increase of the O-H stretching-vibration bandwidth with increasing number of molecules in H-bonded clusters to be explained. Knowledge of the half-width of the OH stretching-vibration absorption band in the dimer and the number of H-bonds in the analyzed cluster is suffi cient in the zeroth-order approximation to estimate the O-H stretching-absorption bands in clusters containing several molecules. Good agreement between the calculated and published experimental half-widths of the OH stretching-vibration absorption bands in MeOH and PrOH clusters was obtained using this approach.

  • 25.
    Ranganathan, Anirudh
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    The impact of GPCR structures on understanding receptor function and ligand binding2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    G protein-coupled receptors (GPCRs) form the largest superfamily of eukaryotic membrane proteins and are responsible for the action of nearly 30% of all marketed drugs. For a long period, efforts to study these receptors were limited by the paucity of atomic-resolution structural information. Numerous receptors spread across the GPCR superfamily have recently been crystallized, revealing crucial clues about receptor function and ligand recognition. The work in this thesis has primarily focused on using computational techniques to capitalize on this increasing amount of structural information. In papers I, II, and III protocols were developed to identify novel ligands for pharmaceutically important targets from in silico screens of large chemical libraries. In these papers, the fragment-based lead discovery (FBLD) approach was evaluated for GPCR targets using molecular docking screens. The high hit-rates obtained in these studies indicate promise for the use of computational approaches for fragment screening. In paper IV, molecular dynamics was used to identify a possible role for a conserved ionizable residue (Asp792.50) as a protonation switch during the activation process of the β2 adrenergic receptor. Analyses from this paper indicated that this residue could also perform a similar function in other class A GPCRs. Papers V and VI detail the modeling strategy followed during the GPCR Dock 2013 assessment to blindly predict the structure of two serotonin receptor subtypes (5-HT1B and 5-HT2B) bound to ergotamine. The developed ligand-steered homology modeling protocol was largely successful resulting in the best-ranked predictions for the 5-HT1B subtype. It is hoped that the work described in this thesis has highlighted the potential for structure-based computational approaches to identify novel ligands for important pharmaceutical targets and improve understanding of GPCR function.

  • 26.
    Ranganathan, Anirudh
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab). Stanford University, USA.
    Dror, Ron O.
    Carlsson, Jens
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab). Stanford University, USA .
    Insights into the Role of Asp79(2.50) in beta(2) Adrenergic Receptor Activation from Molecular Dynamics Simulations2014In: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 53, no 46, p. 7283-7296Article in journal (Refereed)
    Abstract [en]

    Achieving a molecular-level understanding of G-protein-coupled receptor (GPCR) activation has been a long-standing goal in biology and could be important for the development of novel drugs. Recent breakthroughs in structural biology have led to the determination of high-resolution crystal structures for the beta(2) adrenergic receptor (beta(2)AR) in inactive and active states, which provided an unprecedented opportunity to understand receptor signaling at the atomic level. We used molecular dynamics (MD) simulations to explore the potential roles of ionizable residues in beta(2)AR activation. One such residue is the strongly conserved Asp79(2.50), which is buried in a transmembrane cavity and becomes dehydrated upon beta(2)AR activation. MD free energy calculations based on beta(2)AR crystal structures suggested an increase in the population of the protonated state of Asp79(2.50) upon activation, which may contribute to the experimentally observed pH-dependent activation of this receptor. Analysis of MD simulations (in total >100 mu s) with two different protonation states further supported the conclusion that the protonated Asp79(2.50) shifts the conformation of the beta(2)AR toward more active-like states. On the basis of our calculations and analysis of other GPCR crystal structures, we suggest that the protonation state of Asp(2.50) may act as a functionally important microswitch in the activation of the beta(2)AR and other class A receptors.

  • 27.
    Rodriguez, David
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab). Swedish e-Science Research Center (SeRC), Sweden.
    Ranganathan, Anirudh
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab). Swedish e-Science Research Center (SeRC), Sweden.
    Carlsson, Jens
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab). Swedish e-Science Research Center (SeRC), Sweden.
    Strategies for Improved Modeling of GPCR-Drug Complexes: Blind Predictions of Serotonin Receptors Bound to Ergotamine2014In: Journal of Chemical Information and Modeling, ISSN 1549-9596, E-ISSN 1549-960X, Vol. 54, no 7, p. 2004-2021Article in journal (Refereed)
    Abstract [en]

    The recent increase in the number of atomic-resolution structures of G protein-coupled receptors (GPCRs) has contributed to a deeper understanding of ligand binding to several important drug targets. However, reliable modeling of GPCR-ligand complexes for the vast majority of receptors with unknown structure remains to be one of the most challenging goals for computer-aided drug design. The GPCR Dock 2013 assessment, in which researchers were challenged to predict the crystallographic structures of serotonin 5-HT1B and 5-HT2B receptors bound to ergotamine, provided an excellent opportunity to benchmark the current state of this field. Our contributions to GPCR Dock 2013 accurately predicted the binding mode of ergotamine with RMSDs below 1.8 angstrom for both receptors, which included the best submissions for the S-HT1B complex. Our models also had the most accurate description of the binding sites and receptor ligand contacts. These results were obtained using a ligand-guided homology modeling approach, which combines extensive molecular docking screening with incorporation of information from multiple crystal structures and experimentally derived restraints. In this work, we retrospectively analyzed thousands of structures that were generated during the assessment to evaluate our modeling strategies. Major contributors to accuracy were found to be improved modeling of extracellular loop two in combination with the use of molecular docking to optimize the binding site for ligand recognition. Our results suggest that modeling of GPCR-drug complexes has reached a level of accuracy at which structure-based drug design could be applied to a large number of pharmaceutically relevant targets.

  • 28.
    Roos, Katarina
    Stockholm University, Faculty of Science, Department of Physics.
    Manganese and Iron Heterodimers and Homodimers in Enzymes: Insights from Density Functional Theory2012Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The enzyme ribonucleotide reductase (RNR) catalyzes the reduction of ribonucleotides to deoxyribonucleotides, the building blocks of DNA, and is essential for all organisms. Canonical class I RNR R2 proteins use a diiron cofactor to generate a tyrosyl radical, which is required for catalysis. Recent discoveries have established that the different subgroups of class I RNR employ different metal cofactors. Class Ib R2 (R2F) utilizes a dimanganese cofactor and a flavoprotein to generate the tyrosyl radical. Class Ic R2 (R2c) lacks the radical-bearing tyrosine, and instead has an oxidized heterodinuclear manganese-iron center, the first known redox active MnFe cofactor. A second group of MnFe proteins with different functions, denoted R2-like ligand binding oxidases (R2lox), was later identified. R2lox proteins are capable of performing two-electron oxidations and are believed to be hydrocarbon oxidases. In the present thesis density functional theory, a quantum mechanical method, is employed to study the manganese and iron heterodimers and homodimers in the R2 and R2lox proteins, with the aim to shed light on the mechanistic details and stress the main features of the alternative metal centers. Some of the questions addressed are the radical generation with the homodimers and heterodimer in R2, the radical transfer between R2 and the RNR catalytic subunit, and the function of R2lox. A Mn(IV)Fe(III) state is shown to be an equally strong oxidant as a tyrosyl radical, giving a rationalization for the presence of the heterodimer in R2c. A reaction mechanism for the formation of an unprecedented tyrosine-valine crosslink catalyzed by the heterodimer in R2lox is modeled, and the potential of the protein to perform hydroxylations of hydrocarbons based on calculated barriers for methane hydroxylation is discussed. An energetically possible reaction mechanism is suggested for activation of dimanganese R2F by hydrogen peroxide, and a hypothetical role of the flavoprotein in radical generation is proposed.

  • 29.
    Roos, Katarina
    et al.
    Stockholm University, Faculty of Science, Department of Physics.
    Blomberg, Margareta R. A.
    Stockholm University, Faculty of Science, Department of Physics.
    Siegbahn, Per E. M.
    Stockholm University, Faculty of Science, Department of Physics.
    Formation of the Unusual Tyrosine-Valine Crosslink in the Manganese-Iron Heterodimer Oxidase from Mycobacterium tuberculosisManuscript (preprint) (Other academic)
  • 30.
    Rudbeck, Maria
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Basis Set Dependence of Phosphate Frequencies in Density Functional Theory Calculations2012In: International Journal of Quantum Chemistry, ISSN 0020-7608, E-ISSN 1097-461X, Vol. 112, no 11, p. 2435-2439Article in journal (Refereed)
    Abstract [en]

    The addition of extravalence, polarization and diffuse functions, were studied in order to conclude how they affect the PO stretching frequencies of several biological relevant phosphate molecules. The results show that the polarization and the diffuse functions have opposite effects on the frequencies: the polarization functions downshift while the diffuse functions upshift the frequencies. The effect of the valence functions was more difficult to interpret. The effect of the conductor-like screening model (CPCM)-continuum model was also studied. The results show that the CPCM-continuum model has a substantial effect on the frequencies for these small molecules. The continuum model's efficiency is mainly due to its effect on the geometries and not on the frequencies.

  • 31.
    RUDBECK, Maria
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    The Beauty of the Bitter Devils: A Theoretical Study on Phosphate Molecules2011Manuscript (preprint) (Other academic)
  • 32.
    Rudbeck, Maria
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    The Beauty of the Bitter Devils: A Theoretical Study on Phosphate Molecules2011Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Phosphate transfer reactions are catalyzed by a large number of enzymes comprising kinases, mutases and phosphatases. These enzymes play a fundamental role in controlling numerous life processes and it is therefore important to understand the origin of their potent catalytic power. An example is the Ca2+-ATPase. In the E2P-state, this enzyme hydrolyses the phosphorylated amino acid, Asp351, 106 to 107 fold faster than when the model compound, acetyl phosphate, is hydrolyzed in in water.This thesis explores the catalytic power of Ca2+-ATPase using theoretical method based on quantum mechanics. The studies of this protein were made by performing quantum chemical calculations on models of phosphoric monoesters as well as on the explicit reaction pathway of the hydrolysis. The studies show the importance of electrostatic interactions as well as the role of the specific active site residue Glu183, a residue that acts as a base in the catalytic pathway. Furthermore, based on the calculations, the interpretation of the experimental infrared spectrum of the E2P-state of Ca2+-ATPase, could be further elucidated as well as modified.The experimental infrared spectrum of phosphoenol pyruvate in water has also been elucidated through calculations. This molecule is converted into pyruvate in the last step of the glycolytic pathway, a reaction that is catalyzed by pyruvate kinase (PK). These results further enabled the interpretation of the experimental spectrum of the PK's catalytic reaction.These two processes, the transport of Ca2+ into the sarcoplasmatic reticulum against a concentration gradient and the glycolysis, are two important actions of a muscle cell.

  • 33.
    Rudbeck, Maria
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Barth, Andreas
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Blomberg, Margareta
    Stockholm University, Faculty of Science, Department of Physics.
    The hydrolysis of E2P of Ca2+-ATPase: A theoretical studyManuscript (preprint) (Other academic)
  • 34.
    Rudbeck, Maria
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Blomberg, Margareta
    Stockholm University, Faculty of Science, Department of Physics.
    Barth, Andreas
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Infrared Spectrum of E2P of Ca2+-ATPaseManuscript (preprint) (Other academic)
  • 35.
    Rudbeck, Maria
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Nilsson Lill, Sten
    Barth, Andreas
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    The influence of the molecular environment on phosphorylated amino acid models: A density functional theory study2012In: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 116, no 9, p. 2751-2757Article in journal (Refereed)
    Abstract [en]

    A protein environment can affect the structure and charge distribution of substrate molecules. Here, the structure and partial charges were studied for different phosphorylated amino acid models in varying environments using density functional theory. The three systems investigated, acetyl phosphate, methyl phosphate, and p-tolyl phosphate are representative models for aspartyl phosphate, serine or threonine phosphate, and tyrosine phosphate, respectively. Combined with the CPCM continuum model, explicit HF and H2O molecules were added in order to model environmental effects and interactions that may occur in a protein matrix. We show how the different interactions affect the scissile P–O(R) bond and that the elongation can be explained by an anomeric effect. An increasing scissile bond length will result in transfer of negative charge to the leaving group and in a widening of the angle between the terminal oxygens of the phosphate molecule, features that can expose the phosphate group to attacking nucleophiles. Lastly, calculations were performed on the active site of the Ca2+-ATPase E2P intermediate, which provide an example of how a protein environment facilitates the formation of a destabilized ground state

  • 36.
    Ruipérez, Fernando
    et al.
    Stockholm University, Faculty of Science, Department of Physics.
    Danilo, Cécile
    Laboratoire PhLAM, Université des Sciences et Technologies de Lille 1.
    Real, Florent
    Laboratoire PhLAM, Université des Sciences et Technologies de Lille 1.
    Flament, Jean-Pierre
    Laboratoire PhLAM, Université des Sciences et Technologies de Lille 1.
    Vallet, Valérie
    Laboratoire PhLAM, Université des Sciences et Technologies de Lille 1.
    Wahlgren, Ulf
    Stockholm University, Faculty of Science, Department of Physics.
    An ab initio theoretical study of the electronic structure of UO2+ and [UO2(CO3)3]5-2009In: Journal of Physical Chemistry A, ISSN 1089-5639, E-ISSN 1520-5215, Vol. 113, p. 1420-1428Article in journal (Refereed)
    Abstract [en]

    The electronic spectra up to 50000 cm-1 of uranyl(V) both as a bare ion, UO21, and coordinated with three carbonate ligands, [UO2(CO3)3]5-, are presented. Solvent effects were treated by a nonequilibrium continuum solvent model. The transition energies were obtained at the spin-orbit level using relativistic wave function based multiconfigurational methods such as the complete active space self-consistent field method (CASSCF) and the complete active space with second-order perturbation theory (CASPT2) followed by a calculation of the spin-orbit effects at the variation-perturbation level. Earlier relativistic intermediate Hamiltonian Fock space coupled-cluster calculations on the spectrum of the bare uranyl(V) ion were extended to investigate the influence of electron correlation effects on spacings between the electronic states. This study is an attempt to contribute to an enhanced understanding of the electronic structure of actinyl ions. Both spectra show transitions within nonbonding orbitals and between nonbonding and antibonding orbitals as well as charge transfers from the uranyl oxygens to uranium. The ground state in UO2+ is found to be 2Φ5/2u, corresponding to the σu2φu1 configuration, while in [UO2(CO3)3]5-, it is 23/2u, arising from the σu2δu1 configuration. It is remarkable that the excited state corresponding to an excitation from the nonbonding δu to the uranyl antibonding 3πu* molecular orbital is significantly lower in energy in the carbonate complex, 6623 cm-1, than that in the bare ion, 17908 cm-1. The first ligand (carbonate) to metal charge-transfer excitation is estimated to occur above 50000 cm-1. The reported results compare favorably with experiment when available.

  • 37.
    Ruipérez, Fernando
    et al.
    Stockholm University, Faculty of Science, Department of Physics.
    Wahlgren, Ulf
    Stockholm University, Faculty of Science, Department of Physics.
    Charge transfer in uranyl(VI) halides [UO2X4]2- (X = F, Cl, Br and I). A quantum chemical study of the absorption spectraIn: Journal of Physical Chemistry A, ISSN 1089-5639, E-ISSN 1520-5215Article in journal (Refereed)
    Abstract [en]

    The electronic spectra of uranyl(VI) coordinated with four equatorial halide ligands, [UO2X4]2- (X = F, Cl, Br and I), have been calculated at the all-electron level using the multiconfigurational CASPT2 method, with spin-orbit coupling included through the variational-perturbational method. The halide-to-uranyl charge-transfer states were taken into account in the calculation by including ligand orbitals in the active space. In order to do that, it is assumed that the charge transfer takes place from only one of the four ligands. Two models which in principle can describe this were investigated: the first one makes use of a localizing technique and the second one replaces three ligands by ab initio model potentials (AIMPs). The basis set dependence was investigated by using two different basis sets for the halides, of triple-ζ and quadruple-ζ quality. The localization procedure turned out to be strongly basis set dependent, and the most stable results were obtained with ab initio model potentials. The ground state is a closed shell singlet state, and the first excitation is from the bonding σu orbital on uranyl to the nonbonding δu orbitals, except for the [UO2I4]2− complex, where the first excited state has a mixed character of charge transfer from the I and the σu1φu1 configuration. In [UO2F4]2− there is no charge transfer excitation below 50000 cm−1 , while in [UO2Cl4]2− it appears around 33000 cm−1 and in [UO2Br4]2− around 23000 cm−1 . A blueshift of the spectra, from F to I, is observed. The calculations compare reasonably well with available experimental results.

  • 38.
    Schwaiger, Christine S.
    et al.
    Theoretical and Computational Biophysics, Department of Theoretical Physics, Royal Institute of Technology.
    Bjelkmar, Pär
    Theoretical and Computational Biophysics, Department of Theoretical Physics, Royal Institute of Technology.
    Hess, Berk
    Theoretical and Computational Biophysics, Department of Theoretical Physics, Royal Institute of Technology.
    Lindahl, Erik
    Theoretical and Computational Biophysics, Department of Theoretical Physics, Royal Institute of Technology.
    310-Helix Conformation Facilitates the Transition of a Voltage Sensor S4 Segment toward the Down State2011In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 100, no 6, p. 1446-1454Article in journal (Refereed)
    Abstract [en]

    The activation of voltage-gated ion channels is controlled by the S4 helix, with arginines every third residue. The x-ray structures are believed to reflect an open-inactivated state, and models propose combinations of translation, rotation, and tilt to reach the resting state. Recently, experiments and simulations have independently observed occurrence of 310-helix in S4. This suggests S4 might make a transition from α- to 310-helix in the gating process. Here, we show 310-helix structure between Q1 and R3 in the S4 segment of a voltage sensor appears to facilitate the early stage of the motion toward a down state. We use multiple microsecond-steered molecular simulations to calculate the work required for translating S4 both as α-helix and transformed to 310-helix. The barrier appears to be caused by salt-bridge reformation simultaneous to R4 passing the F233 hydrophobic lock, and it is almost a factor-two lower with 310-helix. The latter facilitates translation because R2/R3 line up to face E183/E226, which reduces the requirement to rotate S4. This is also reflected in a lower root mean-square deviation distortion of the rest of the voltage sensor. This supports the 310 hypothesis, and could explain some of the differences between the open-inactivated- versus activated-states.

  • 39.
    Siegbahn, Per
    et al.
    Stockholm University, Faculty of Science, Department of Physics.
    Blomberg, Margareta
    Stockholm University, Faculty of Science, Department of Physics.
    The Combined Picture from Theory and Experiments on Water Oxidation, Oxygen Reduction and Proton Pumping2009In: Dalton Transactions, ISSN 1477-9226, E-ISSN 1477-9234, no 30, p. 5832-5840Article in journal (Refereed)
    Abstract [en]

     

    In order to illustrate how theory and experiments can be combined, examples are taken from two projects that have been going on for a decade. The goal is to obtain the full mechanistic picture of wateroxidation in photosystem II and proton pumping in cytochrome c oxidase. It is argued that for obtaining a complete description of these processes, both experiments and theoretical calculations are needed. It is obvious that there are aspects, which are out of reach for computations, but there are also key aspects that can not be obtained by experiments. This concerns very short-lived species but also, in the case of photosynthesis in particular, structural information that is presently out of reach. The main contributions from theory in the present cases, is for photosynthesis a mechanism for O–O bond formation including new and improved structures for all S-states, and for proton pumping a plausible and simple mechanism for proton gating. The examples also illustrate that sometimes rather qualitative experimental information can be of highest importance.

  • 40.
    Siegbahn, Per E.M.
    et al.
    Stockholm University, Faculty of Science, Department of Physics.
    Blomberg, Margareta R.A.
    Stockholm University, Faculty of Science, Department of Physics.
    On the Proton Pumping Mechanism in Cytochrome c Oxidase2008In: Journal of Physical Chemistry A, ISSN 1089-5639, E-ISSN 1520-5215, Vol. 112, p. 12772-12780Article in journal (Refereed)
    Abstract [en]

    Two different issues, important for the pumping mechanism of cyctochrome c oxidase, have been addressed in the present study. One of them concerns the nature of two key proton transfer transition states. A simple electrostatic model is used to suggest that the transition state (TS) for transfer to the pump-site should be positively charged, while the one for transfer to the binuclear center should be charge-neutral. The character of the former TS will guarantee that the protons will be pumped to the outside and not return to the inside, while the neutral character of the latter one will allow transfer with a sufficiently low barrier. In the simple electrostatic analysis, leading to this qualitative picture of the pumping process, the results from the kinetic experiments are strictly followed, but it is at least as important to follow the fundamental requirements for pumping. In this perspective, the uncertainties in the quantitative analysis should be rather unimportant for the emerging qualitative picture of the pumping mechanism. The second problem addressed concerns the purpose of the K-channel. It is argued that the reason for the presence of the K-channel could be that protons cannot pass through the binuclear center at some stage of pumping. Barriers and water binding energies were computed using hybrid density functional theory (DFT) to investigate this question.

  • 41.
    Stenrup, Michael
    Stockholm University, Faculty of Science, Department of Physics.
    Photo-induced molecular processes and charge recombination reactions driven by non-adiabatic couplings2012Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    This thesis is based on a number of theoretical studies of molecular processes in which non-adiabatic effects play a crucial role. The main part is devoted to the photophysics and photochemistry of five-membered aromatic heterocyclic compounds, with particular focus on furan and thiophene. These species absorb light in the UV region of the spectrum, but exhibits neither fluorescence nor phosphorescence. A plausible explanation for this is the presence of very fast radiationless deactivation mechanisms that depopulate the excited states before emission can occur. In the present thesis, several possible such mechanisms are considered based on the results of static electronic structure calculations as well as mixed quantum-classical dynamics simulations. A common feature of the investigated pathways is the presence of easily accessible conical intersections (surface crossings) through which non-adiabatic population transfer to the electronic ground state may take place. Also considered in the present work are the bond-breaking/bond-forming processes that are expected to follow once the ground state has been reached.

    Another prominent example of non-adiabatic processes is charge recombination reactions involving either two oppositely charged ions or a cation and an electron. Here, the reactants and products belong to different electronic states of the system as a whole and therefore a non-adiabatic transition is necessary for the recombination to occur. Two such processes are considered in the present thesis; mutual neutralization of oppositely charged hydrogen ions and dissociative recombination of the formyl and iso-formyl cations. The cross sections (rate coefficients) and underlying mechanisms of these reactions are investigated at a fully quantum mechanical level.

  • 42.
    Stenrup, Michael
    Stockholm University, Faculty of Science, Department of Physics.
    Radiationless deactivation and intermediate formation in photo-excited thiopheneManuscript (preprint) (Other academic)
  • 43.
    Stenrup, Michael
    Stockholm University, Faculty of Science, Department of Physics.
    Theoretical study of the radiationless deactivation mechanisms of photo-excited thiophene2012In: Chemical Physics, ISSN 0301-0104, E-ISSN 1873-4421, Vol. 397, p. 18-25Article in journal (Refereed)
    Abstract [en]

    The radiationless deactivation mechanisms of photo-excited thiophene have been studied using the multi-reference second-order perturbation theory and linear response coupled cluster methods. The electronic spectrum has been established and various minimum energy structures and conical intersections involving the ground and lowest singlet excited states have been characterized. Simplified reaction paths connecting the optimized geometries have been calculated as well. Based on these investigations, several deactivation mechanisms have been identified leading from the lowest bright 1ππ states back to the electronic ground state. The excited state depletion in each case is possible due to the existence of low-lying conical intersections formed by either cleavage of one of the CS bonds or out-of-plane deformations of the aromatic ring. The deactivation mechanisms suggested in this work should provide some very efficient decay channels after excitation into the first UV absorption band of thiophene, and are good candidates to explain why this compound is non-fluorescent.

  • 44.
    Stenrup, Michael
    et al.
    Stockholm University, Faculty of Science, Department of Physics.
    Larson, Åsa
    Stockholm University, Faculty of Science, Department of Physics.
    A computational study of radiationless deactivation mechanisms of furan2011In: Chemical Physics, ISSN 0301-0104, E-ISSN 1873-4421, Vol. 379, no 1-3, p. 6-12Article in journal (Refereed)
    Abstract [en]

    Possible mechanisms for the radiationless deactivation of photo-excited furan have been investigated using high-level electronic structure methods. Two different conical intersections between the S0 and S1 electronic states have been characterized, both involving various degrees of CO bond cleavage. One of these corresponds to a planar ring-opened structure and the other to an asymmetric ring-puckered structure. Calculations have been performed in order to establish the vertical electronic spectrum and to investigate the behaviour of the potential energy surfaces as the intersections are approached. The present results indicate that both crossings can be accessed through exothermic and barrierless processes after vertical excitation into the optically bright S2(ππ∗) state. These features make them good candidates to account for efficient radiationless deactivation in furan. The deactivation pathways considered in the present work are close analogues of those previously described for other five-membered heterocycles.

  • 45.
    Svensson, Mats
    Stockholm University, Faculty of Science.
    Modelling organometallic reactions: a quantum chemical study of some oxidative addition reactions1994Doctoral thesis, comprehensive summary (Other academic)
  • 46.
    Todde, Guido
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK).
    Exploring Protein Functions by Molecular Modelling2015Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Proteins are one of the most important families of biological macromolecules. Proteins can assume many different structures. This makes them perfect to serve a wide range of functions in all organisms. In the last decades, molecular modeling has become an important and powerful tool in the investigation of biological systems. Adopting different computational methods many protein functions and structure related problems can be explored.

    This thesis focuses on three different protein issues. The structural changes induced by high temperature on a large enzyme were investigated simulating the denaturation of glucose oxidase. Molecular dynamics (MD) simulations at different high temperatures were performed. The transition state of the denaturation process was found and the relative ensemble of structures characterized. Different protein properties were analyzed and found in agreement with experimental and theoretical data. Moreover the breaking points of the protein were localized and point mutations on the protein sequence were suggested.

    Antifreeze proteins (AFP) allow different organisms to survive in subzero environments. These proteins lower the freezing point of physiological fluids. MD simulations of the snow flea AFP (sfAFP) in water have shown partial instability of the protein structure. When attached to different ice planes at the ice/water interface, the sfAFP induces local ice melting. AFPs are divided into two categories: hyperactive and moderately active depending on their antifreeze power. The water diffusion profile of ice/water systems containing one protein from each family were compared. The ice/water interface width was found to be broadened to different extent by the two proteins, while a control protein (ubiquitin) did not affect the interface thickness.

    Hemoglobin is the oxygen carrier in all vertebrates. Mutation along the protein sequence can alter the protein functionality and its capability of binding molecular oxygen. Density Functional Theory methods were applied in the calculation of the oxygen binding energy of the wild type hemoglobin and four other variants. Evaluations on the electronic structures and on the binding energies of the different hemoglobin variants suggest that perhaps none of the mutated hemoglibins efficiently bind oxygen.

  • 47.
    Todde, Guido
    et al.
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK).
    Hovmöller, Sven
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK).
    Laaksonen, Aatto
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK). Stockholm University, Science for Life Laboratory (SciLifeLab). Wallenberg Research Centre at Stellenbosch University, South Africa.
    Influence of Antifreeze Protein on the Ice/Water Interface2015In: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 119, no 8, p. 3407-3413Article in journal (Refereed)
    Abstract [en]

    Antifreeze proteins (AFP) are responsible for the survival of several species, ranging from bacteria to fish, that encounter subzero temperatures in their living environment. AFPs have been divided into two main families, moderately and hyperactive, depending on their thermal hysteresis activity. We have studied one protein from both families, the AFP from the snow flea (sfAFP) and from the winter flounder (wfAFP), which belong to the hyperactive and moderately active family, respectively. On the basis of molecular dynamics simulations, we have estimated the thickness of the water/ice interface for systems both with and without the AFPs attached onto the ice surface. The calculation of the diffusion profiles along the simulation box allowed us to measure the interface width for different ice planes. The obtained widths clearly show a different influence of the two AFPs on the ice/water interface. The different impact of the AFPs here studied on the interface thickness can be related to two AFPs properties: the protein hydrophobic surface and the number of hydrogen bonds that the two AFPs faces form with water molecules.

  • 48.
    Todde, Guido
    et al.
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK).
    Hovmöller, Sven
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK).
    Laaksonen, Aatto
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK).
    The Influence of Mutations at the Proximal Histidine Position on the Fe-O2 Bond in Hemoglobin from Density Functional TheoryManuscript (preprint) (Other academic)
  • 49. Wernet, Philippe
    et al.
    Kunnus, Kristjan
    Schreck, Simon
    Quevedo, Wilson
    Kurian, Reshmi
    Techert, Simone
    de Groot, Frank M. F.
    Odelius, Michael
    Stockholm University, Faculty of Science, Department of Physics.
    Föhlisch, Alexander
    Dissecting Local Atomic and Intermolecular Interactions of Transition-Metal Ions in Solution with Selective X-ray Spectroscopy2012In: Journal of Physical Chemistry Letters, ISSN 1948-7185, E-ISSN 1948-7185, Vol. 3, no 23, p. 3448-3453Article in journal (Refereed)
    Abstract [en]

    Determining covalent and charge-transfer contributions to bonding in solution has remained an experimental challenge. Here, the quenching of fluorescence decay channels as expressed in dips in the L-edge X-ray spectra of solvated 3d transition-metal ions and complexes was reported as a probe. With a full set of experimental and theoretical ab initio L-edge X-ray spectra of aqueous Cr3+, including resonant inelastic X-ray scattering, we address covalency and charge transfer for this prototypical transition-metal ion in solution. We dissect local atomic effects from intermolecular interactions and quantify X-ray optical effects. We find no evidence for the asserted ultrafast charge transfer to the solvent and show that the dips are readily explained by X-ray optical effects and local atomic state dependence of the fluorescence yield. Instead, we find, besides ionic interactions, a covalent contribution to the bonding in the aqueous complex of ligand-to-metal charge-transfer character

  • 50.
    Wilson, Michael A.
    et al.
    Department of Pharmaceutical Chemistry, University of California, San Francisco.
    Wei, Chenyu
    Department of Pharmaceutical Chemistry, University of California, San Francisco.
    Bjelkmar, Pär
    MS 239-4, Exobiology Branch, NASA Ames Research Center, Moffet Field, California.
    Wallace, B. A.
    Department of Crystallography, Institute of Structural and Molecular Biology, Birkbeck College, University of London.
    Pohorille, Andrew
    Department of Pharmaceutical Chemistry, University of California, San Francisco.
    Molecular Dynamics Simulation of the Antiamoebin Ion Channel: Linking Structure and Conductance2011In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 100, no 10, p. 2394-402Article in journal (Refereed)
    Abstract [en]

    Molecular-dynamics simulations were carried out to ascertain which of the potential multimeric forms of the transmembrane peptaibol channel, antiamoebin, is consistent with its measured conductance. Estimates of the conductance obtained through counting ions that cross the channel and by solving the Nernst-Planck equation yield consistent results, indicating that the motion of ions inside the channel can be satisfactorily described as diffusive. The calculated conductance of octameric channels is markedly higher than the conductance measured in single channel recordings, whereas the tetramer appears to be nonconducting. The conductance of the hexamer was estimated to be 115 ± 34 pS and 74 ± 20 pS, at 150 mV and 75 mV, respectively, in satisfactory agreement with the value of 90 pS measured at 75 mV. On this basis, we propose that the antiamoebin channel consists of six monomers. Its pore is large enough to accommodate K+ and Cl with their first solvation shells intact. The free energy barrier encountered by K+ is only 2.2 kcal/mol whereas Cl encounters a substantially higher barrier of nearly 5 kcal/mol. This difference makes the channel selective for cations. Ion crossing events are shown to be uncorrelated and follow Poisson statistics.

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