| 1. |
- Ames, William, et al.
(författare)
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Theoretical Evaluation of Structural Models of the S(2) State in the Oxygen Evolving Complex of Photosystem II : Protonation States and Magnetic Interactions
- 2011
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Ingår i: Journal of the American Chemical Society. - : American Chemical Society (ACS). - 0002-7863 .- 1520-5126. ; 133:49, s. 19743-19757
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Tidskriftsartikel (refereegranskat)abstract
- Protonation states of water ligands and oxo bridges are intimately involved in tuning the electronic structures and oxidation potentials of the oxygen evolving complex (OEC) in Photosystem II, steering the mechanistic pathway, which involves at least five redox state intermediates S(n) (n = 0-4) resulting in the oxidation of water to molecular oxygen. Although protons are practically invisible in protein crystallography, their effects on the electronic structure and magnetic properties of metal active sites can be probed using spectroscopy. With the twin purpose of aiding the interpretation of the complex electron paramagnetic resonance (EPR) spectroscopic data of the OEC and of improving the view of the cluster at the atomic level, a complete set of protonation configurations for the S(2) state of the OEC were investigated, and their distinctive effects on magnetic properties of the cluster were evaluated. The most recent X-ray structure of Photosystem II at 1.9 Å resolution was used and refined to obtain the optimum structure for the Mn(4)O(5)Ca core within the protein pocket. Employing this model, a set of 26 structures was constructed that tested various protonation scenarios of the water ligands and oxo bridges. Our results suggest that one of the two water molecules that are proposed to coordinate the outer Mn ion (Mn(A)) of the cluster is deprotonated in the S(2) state, as this leads to optimal experimental agreement, reproducing the correct ground state spin multiplicity (S = 1/2), spin expectation values, and EXAFS-derived metal-metal distances. Deprotonation of Ca(2+)-bound water molecules is strongly disfavored in the S(2) state, but dissociation of one of the two water ligands appears to be facile. The computed isotropic hyperfine couplings presented here allow distinctions between models to be made and call into question the assumption that the largest coupling is always attributable to Mn(III). The present results impose limits for the total charge and the proton configuration of the OEC in the S(2) state, with implications for the cascade of events in the Kok cycle and for the water splitting mechanism.
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| 2. |
- Andersson, Ida E., 1982-, et al.
(författare)
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(E)-Alkene and Ethylene Isosteres Substantially Alter the Hydrogen-Bonding Network in Class II MHC Aq/Glycopeptide Complexes and Affect T-Cell Recognition
- 2011
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Ingår i: Journal of the American Chemical Society. - : American Chemical Society. - 0002-7863 .- 1520-5126. ; 133:36, s. 14368-14378
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Tidskriftsartikel (refereegranskat)abstract
- The structural basis for antigen presentation by class II major histocompatibility complex (MHC) proteins to CD4(+) T-cells is important for understanding and possibly treating autoimmune diseases. In the work described in this paper, (E)-alkene and ethylene amide-bond isosteres were used to investigate the effect of removing hydrogen-bonding possibilities from the CII259-270 glycopeptide, which is bound by the arthritis-associated murine A(q) class II MHC protein. The isostere-modified glycopeptides showed varying and unexpectedly large losses of A(q) binding that could be linked to the dynamics of the system. Molecular dynamics (MD) simulations revealed that the backbone of CII259-270 and the A(q) protein are able to form up to 11 hydrogen bonds, but fewer than this number are present at any one time. Most of the strong hydrogen-bond interactions were formed by the N-terminal part of the glycopeptide, i.e., in the region where the isosteric replacements were made. The structural dynamics also revealed that hydrogen bonds were strongly coupled to each other; the loss of one hydrogen-bond interaction had a profound effect on the entire hydrogen-bonding network. The A(q) binding data revealed that an ethylene isostere glycopeptide unexpectedly bound more strongly to A(q) than the corresponding (E)-alkene, which is in contrast to the trend observed for the other isosteres. Analysis of the MD trajectories revealed that the complex conformation of this ethylene isostere was structurally different and had an altered molecular interaction pattern compared to the other A(q)/glycopeptide complexes. The introduced amide-bond isosteres also affected the interactions of the glycopeptide/A(q) complexes with T-cell receptors. The dynamic variation of the patterns and strengths of the hydrogen-bond interactions in the class II MHC system is of critical importance for the class II MHC/peptide/TCR signaling system.
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| 3. |
- Bergström, Fredrik, et al.
(författare)
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Dimers of dipyrrometheneboron difluoride (BODIPY) with light spectroscopic applications in chemistry and biology.
- 2002
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Ingår i: Journal of the American Chemical Society. - 0002-7863 .- 1520-5126. ; 124:2, s. 196-204
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Tidskriftsartikel (refereegranskat)abstract
- A ground-state dimer (denoted D(I)) exhibiting a strong absorption maximum at 477 nm (epsilon = 97 000 M(-1)cm(-1)) can form between adjacent BODIPY groups attached to mutant forms of the protein, plasminogen activator inhibitor type 1 (PAI-1). No fluorescence from excited D(I) was detected. A locally high concentration of BODIPY groups was also achieved by doping lipid phases (micelles, vesicles) with BODIPY-labeled lipids. In addition to an absorption band located at about 480 nm, a new weak absorption band is also observed at ca. 570 nm. Both bands are ascribed to the formation of BODIPY dimers of different conformation (D(I) and D(II)). Contrary to D(I) in PAI-1, the D(II) aggregates absorbing at 570 nm are emitting light observed as a broad band centered at about 630 nm. The integrated absorption band of D(I) is about twice that of the monomer, which is compatible with exciton coupling within a dimer. The Förster radius of electronic energy transfer between a BODIPY excited monomer and the ground-state dimer (D(I)()) is 57 +/- 2 A. A simple model of exciton coupling suggests that in D(I) two BODIPY groups are stacked on top of each other in a sandwich-like configuration with parallel electronic transition dipoles. For D(II) the model suggests that the S(0) --> S(1) transition dipoles are colinear. An explanation for the previously reported (J. Am. Chem. Soc. 1994, 116, 7801) exceptional light spectroscopic properties of BODIPY is also presented. These are ascribed to the extraordinary electric properties of the BODIPY chromophore. First, changes of the permanent electric dipole moment (Delta(mu) approximately -0.05 D) and polarizability (-26 x 10(-40) C m(2) V(-1)) between the ground and the first excited states are small. Second, the S(0) <--> S(1) electronic transition dipole moments are perpendicular to Delta(mu).
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| 4. |
- Bergström, Fredrik, et al.
(författare)
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Dimers of Dipyrrometheneboron Difluoride (BODIPY) with Light Spectroscopic Applications in Chemistry and Biology
- 2002
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Ingår i: Journal of the American Chemical Society. - : American Chemical Society (ACS). - 0002-7863 .- 1520-5126. ; 124:2, s. 196-204
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Tidskriftsartikel (refereegranskat)abstract
- A ground-state dimer (denoted DI) exhibiting a strong absorption maximum at 477 nm ( = 97 000 M-1cm-1) can form between adjacent BODIPY groups attached to mutant forms of the protein, plasminogen activator inhibitor type 1 (PAI-1). No fluorescence from excited DI was detected. A locally high concentration of BODIPY groups was also achieved by doping lipid phases (micelles, vesicles) with BODIPY-labeled lipids. In addition to an absorption band located at about 480 nm, a new weak absorption band is also observed at ca. 570 nm. Both bands are ascribed to the formation of BODIPY dimers of different conformation (DI and DII). Contrary to DI in PAI-1, the DII aggregates absorbing at 570 nm are emitting light observed as a broad band centered at about 630 nm. The integrated absorption band of DI is about twice that of the monomer, which is compatible with exciton coupling within a dimer. The Förster radius of electronic energy transfer between a BODIPY excited monomer and the ground-state dimer (DI) is 57 ± 2 Å. A simple model of exciton coupling suggests that in DI two BODIPY groups are stacked on top of each other in a sandwich-like configuration with parallel electronic transition dipoles. For DII the model suggests that the S0 S1 transition dipoles are collinear. An explanation for the previously reported (J. Am. Chem. Soc. 1994, 116, 7801) exceptional light spectroscopic properties of BODIPY is also presented. These are ascribed to the extraordinary electric properties of the BODIPY chromophore. First, changes of the permanent electric dipole moment ( -0.05 D) and polarizability (-26 × 10-40 C m2 V-1) between the ground and the first excited states are small. Second, the S0 S1 electronic transition dipole moments are perpendicular to .
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| 5. |
- Berner, Andreas, et al.
(författare)
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G4-ligand-conjugated oligonucleotides mediate selective binding and stabilization of individual G4 DNA structures
- 2023
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Ingår i: Journal of the American Chemical Society. - : American Chemical Society (ACS). - 0002-7863 .- 1520-5126. ; 146:10, s. 6926-6935
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Tidskriftsartikel (refereegranskat)abstract
- G-quadruplex (G4) DNA structures are prevalent secondary DNA structures implicated in fundamental cellular functions, such as replication and transcription. Furthermore, G4 structures are directly correlated to human diseases such as cancer and have been highlighted as promising therapeutic targets for their ability to regulate disease-causing genes, e.g., oncogenes. Small molecules that bind and stabilize these structures are thus valuable from a therapeutic perspective and helpful in studying the biological functions of the G4 structures. However, there are hundreds of thousands of G4 DNA motifs in the human genome, and a long-standing problem in the field is how to achieve specificity among these different G4 structures. Here, we developed a strategy to selectively target an individual G4 DNA structure. The strategy is based on a ligand that binds and stabilizes G4s without selectivity, conjugated to a guide oligonucleotide, that specifically directs the G4-Ligand-conjugated oligo (GL-O) to the single target G4 structure. By employing various biophysical and biochemical techniques, we show that the developed method enables the targeting of a unique, specific G4 structure without impacting other off-target G4 formations. Considering the vast amount of G4s in the human genome, this represents a promising strategy to study the presence and functions of individual G4s but may also hold potential as a future therapeutic modality.
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| 6. |
- Bokvist, Marcus, et al.
(författare)
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Misfolding of amyloidogenic proteins at membrane surfaces : the impact of macromolecularcCrowding
- 2007
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Ingår i: Journal of the American Chemical Society. - : American Chemical Society (ACS). - 0002-7863 .- 1520-5126. ; 129:48, s. 14848-14849
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Tidskriftsartikel (refereegranskat)abstract
- The presence of inert macromolecular crowding agents mimics the situation in vivo where amyloidogenic proteins are released into an aqueous, congested intracellular environment. By using the amphiphatic Alzheimer A-protein as the model system, the presence of a three-dimensional macromolecular crowding environment enhanced significantly its misfolding behavior if charged membrane surfaces as two-dimensional aggregation templates were present.
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| 7. |
- Brännström, Kristoffer, et al.
(författare)
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The N-terminal Region of Amyloid β Controls the Aggregation Rate and Fibril Stability at Low pH Through a Gain of Function Mechanism
- 2014
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Ingår i: Journal of the American Chemical Society. - : American Chemical Society (ACS). - 0002-7863 .- 1520-5126. ; 136:31, s. 10956-10964
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Tidskriftsartikel (refereegranskat)abstract
- Alzheimer's disease is linked to a pathological polymerization of the endogenous amyloid β-peptide (Aβ) that ultimately forms amyloid plaques within the human brain. We used surface plasmon resonance (SPR) to measure the kinetic properties of Aβ fibril formation under different conditions during the polymerization process. For all polymerization processes, a critical concentration of free monomers, as defined by the dissociation equilibrium constant (KD), is required for the buildup of the polymer, for example, amyloid fibrils. At concentrations below the KD, polymerization cannot occur. However, the KD for Aβ has previously been shown to be several orders of magnitude higher than the concentrations found in the cerebrospinal and interstitial fluids of the human brain, and the mechanism by which Aβ amyloid forms in vivo has been a matter of debate. Using SPR, we found that the KD of Aβ dramatically decreases as a result of lowering the pH. Importantly, this effect enables Aβ to polymerize within a picomolar concentration range that is close to the physiological Aβ concentration within the human brain. The stabilizing effect is dynamic, fully reversible, and notably pronounced within the pH range found within the endosomal and lysosomal pathways. Through sequential truncation, we show that the N-terminal region of Aβ contributes to the enhanced fibrillar stability due to a gain of function mechanism at low pH. Our results present a possible route for amyloid formation at very low Aβ concentrations and raise the question of whether amyloid formation in vivo is restricted to a low pH environment. These results have general implications for the development of therapeutic interventions.
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| 8. |
- Castronovo, Matteo, et al.
(författare)
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Mechanical stabilization effect of water on a membrane-like system
- 2007
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Ingår i: Journal of the American Chemical Society. - : American Chemical Society (ACS). - 0002-7863 .- 1520-5126. ; 129:9, s. 2636-2641
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Tidskriftsartikel (refereegranskat)abstract
- The penetration resistance of a prototypical model-membrane system (HS−(CH2)11−OH self-assembled monolayer (SAM) on Au(111)) to the tip of an atomic force microscope (AFM) is investigated in the presence of different solvents. The compressibility (i.e., height vs tip load) of the HS−(CH2)11−OH SAM is studied differentially, with respect to a reference structure. The reference consists of hydrophobic alkylthiol molecules (HS−(CH2)17−CH3) embedded as nanosized patches into the hydrophilic SAM by nanografting, an AFM-assisted nanolithography technique. We find that the penetration resistance of the hydrophilic SAM depends on the nature of the solvent and is much higher in the presence of water than in 2-butanol. In contrast, no solvent-dependent effect is observed in the case of hydrophobic SAMs. We argue that the mechanical resistance of the hydroxyl-terminated SAM is a consequence of the structural order of the solvent−SAM interface, as suggested by our molecular dynamics simulations. The simulations show that in the presence of 2-butanol the polar head groups of the HS−(CH2)11−OH SAM, which bind only weakly to the solvent molecules, try to bind to each other, disrupting the local order at the interface. On the contrary, in the presence of water the polar head groups bind preferentially to the solvent that, in turn, mediates the release of the surface strain, leading to a more ordered interface. We suggest that the mechanical stabilization effect induced by water may be responsible for the stability of even more complex, real membrane systems.
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| 9. |
- Cox, Nicholas, et al.
(författare)
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Effect of Ca(2+)/Sr(2+) substitution on the electronic structure of the oxygen-evolving complex of photosystem II : a combined multifrequency EPR, (55)Mn-ENDOR, and DFT study of the S(2) State
- 2011
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Ingår i: Journal of the American Chemical Society. - : American Chemical Society (ACS). - 0002-7863 .- 1520-5126. ; 133:10, s. 3635-3648
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Tidskriftsartikel (refereegranskat)abstract
- The electronic structures of the native Mn(4)O(x)Ca cluster and the biosynthetically substituted Mn(4)O(x)Sr cluster of the oxygen evolving complex (OEC) of photosystem II (PSII) core complexes isolated from Thermosynechococcus elongatus, poised in the S(2) state, were studied by X- and Q-band CW-EPR and by pulsed Q-band (55)Mn-ENDOR spectroscopy. Both wild type and tyrosine D less mutants grown photoautotrophically in either CaCl(2) or SrCl(2) containing media were measured. The obtained CW-EPR spectra of the S(2) state displayed the characteristic, clearly noticeable differences in the hyperfine pattern of the multiline EPR signal [Boussac et al. J. Biol. Chem.2004, 279, 22809-22819]. In sharp contrast, the manganese ((55)Mn) ENDOR spectra of the Ca and Sr forms of the OEC were remarkably similar. Multifrequency simulations of the X- and Q-band CW-EPR and (55)Mn-pulsed ENDOR spectra using the Spin Hamiltonian formalism were performed to investigate this surprising result. It is shown that (i) all four manganese ions contribute to the (55)Mn-ENDOR spectra; (ii) only small changes are seen in the fitted isotropic hyperfine values for the Ca(2+) and Sr(2+) containing OEC, suggesting that there is no change in the overall spin distribution (electronic coupling scheme) upon Ca(2+)/Sr(2+) substitution; (iii) the changes in the CW-EPR hyperfine pattern can be explained by a small decrease in the anisotropy of at least two hyperfine tensors. It is proposed that modifications at the Ca(2+) site may modulate the fine structure tensor of the Mn(III) ion. DFT calculations support the above conclusions. Our data analysis also provides strong support for the notion that in the S(2) state the coordination of the Mn(III) ion is square-pyramidal (5-coordinate) or octahedral (6-coordinate) with tetragonal elongation. In addition, it is shown that only one of the currently published OEC models, the Siegbahn structure [Siegbahn, P. E. M. Acc. Chem. Res.2009, 42, 1871-1880, Pantazis, D. A. et al. Phys. Chem. Chem. Phys.2009, 11, 6788-6798], is consistent with all data presented here. These results provide important information for the structure of the OEC and the water-splitting mechanism. In particular, the 5-coordinate Mn(III) is a potential site for substrate 'water' (H(2)O, OH(-)) binding. Its location within the cuboidal structural unit, as opposed to the external 'dangler' position, may have important consequences for the mechanism of O-O bond formation.
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| 10. |
- Diaz de Grenu, Borja, et al.
(författare)
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Fluorescent Discrimination between Traces of Chemical Warfare Agents and Their Mimics
- 2014
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Ingår i: Journal of the American Chemical Society. - : American Chemical Society (ACS). - 0002-7863 .- 1520-5126. ; 136:11, s. 4125-4128
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Tidskriftsartikel (refereegranskat)abstract
- An array of fluorogenic probes is able to discriminate between nerve agents, sarin, soman, tabun, VX and their mimics, in water or organic solvent, by qualitative fluorescence patterns and quantitative multivariate analysis, thus making the system suitable for the in-the-field detection of traces of chemical warfare agents as well as to differentiate between the real nerve agents and other related compounds.
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