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1.
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2.
  • Larsson, Daniel, 1981- (författare)
  • Exploring the Molecular Dynamics of Proteins and Viruses
  • 2012
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • Knowledge about structure and dynamics of the important biological macromolecules — proteins, nucleic acids, lipids and sugars — helps to understand their function. Atomic-resolution structures of macromolecules are routinely captured with X-ray crystallography and other techniques. In this thesis, simulations are used to explore the dynamics of the molecules beyond the static structures.Viruses are machines constructed from macromolecules. Crystal structures of them reveal little to no information about their genomes. In simulations of empty capsids, we observed a correlation between the spatial distribution of chloride ions in the solution and the position of RNA in crystals of satellite tobacco necrosis virus (STNV) and satellite tobacco mosaic virus (STMV). In this manner, structural features of the non-symmetric RNA could also be inferred.The capsid of STNV binds calcium ions on the icosahedral symmetry axes. The release of these ions controls the activation of the virus particle upon infection. Our simulations reproduced the swelling of the capsid upon removal of the ions and we quantified the water permeability of the capsid. The structure and dynamics of the expanded capsid suggest that the disassembly is initiated at the 3-fold symmetry axis.Several experimental methods require biomolecular samples to be injected into vacuum, such as mass-spectrometry and diffractive imaging of single particles. It is therefore important to understand how proteins and molecule-complexes respond to being aerosolized. In simulations we mimicked the dehydration process upon going from solution into the gas phase. We find that two important factors for structural stability of proteins are the temperature and the level of residual hydration. The simulations support experimental claims that membrane proteins can be protected by a lipid micelle and that a non-membrane protein could be stabilized in a reverse micelle in the gas phase. A water-layer around virus particles would impede the signal in diffractive experiments, but our calculations estimate that it should be possible to determine the orientation of the particle in individual images, which is a prerequisite for three-dimensional reconstruction.
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3.
  • Bárány-Wallje, Elsa, 1979- (författare)
  • Biophysical studies of cell-penetrating peptides and of the RNR inhibitor Sml1
  • 2008
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • Several short peptides, so called cell-penetrating peptides, have the capability to transport large hydrophilic cargos through the cell membrane. The objective is to use these peptides as drug carriers and thereby enhance the uptake of drugs into cells.Three different cell-penetrating peptides are characterized in this thesis. Structure and dynamics of transportan when bound to phospholipid bicelles was determined using NMR. The hydrophobic peptide transportan and its deletion analogue Tp10 both bind to lipid head-group region of the membrane as amphipathic α-helices (papers I & II) and they were found to cause leakage in vesicles (paper IV). The membrane disturbing effect is probably part of how these peptides are translocated through the cell membrane, but also an explanation to why these peptides are found to be toxic in vivo. The high degree of toxicity limits their usefulness. We however also found that the membrane disturbing effect was significantly reduced when a large hydrophilic cargo was attached, which indicates that the properties of the whole peptide-cargo complex has to be taken into account (paper IV).The highly charged cell-penetrating peptide penetratin is not nearly as membrane disturbing as transportan (papers III and IV). Penetratin binds preferably to negatively charged membranes by electrostatic interactions. We used several different techniques to investigate if penetratin could be translocated through membrane model systems. All experiments consistently suggested that penetratin could not be translocated into model systems. It indicates an endocytotic uptake mechanism into cells rather than a direct membrane penetration (paper III). The ribonucleotide reductase inhibitor protein Sml1 was characterized using NMR and CD spectroscopy (paper V). Three different secondary structure elements were found, in agreement with previous NMR studies, but Sml1 does not have a well defined three-dimensional structure in solution. The N-terminus includes an α-helical region between residues 4-14 and we propose that this region interacts with the C-terminal part of the protein in the monomeric form. The N-terminus is also suggested to be a dimerization interface. Dimers are formed at concentrations above 10 µM in solution. The C-terminal region of Sml1 includes an α-helix between residues 61-80 that is crucial for binding and inhibition of RNR.
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4.
  • Bertaccini, Edward J, et al. (författare)
  • Modeling anesthetic binding sites within the glycine alpha one receptor based on prokaryotic ion channel templates : the problem with TM4
  • 2010
  • Ingår i: Journal of chemical information and modeling. - 1549-9596 .- 1549-960X. ; 50:12, s. 2248-2255
  • Tidskriftsartikel (refereegranskat)abstract
    • Ligand-gated ion channels (LGICs) significantly modulate anesthetic effects. Their exact molecular structure remains unknown. This has led to ambiguity regarding the proper amino acid alignment within their 3D structure and, in turn, the location of any anesthetic binding sites. Current controversies suggest that such a site could be located in either an intra- or intersubunit locale within the transmembrane domain of the protein. Here, we built a model of the glycine alpha one receptor (GlyRa1) based on the open-state structures of two new high-resolution ion channel templates from the prokaryote, Gloebacter violaceus (GLIC). Sequence scoring suggests reasonable homology between GlyRa1 and GLIC. Three of the residues notable for modulating anesthetic action are on transmembrane segments 1-3 (TM1-3): (ILE229, SER 267, and ALA 288). They line an intersubunit interface, in contrast to previous models. However, residues from the fourth transmembrane domain (TM4) that are known to modulate a variety of anesthetic effects are quite distant from this putative anesthetic binding site. While this model can account for a large proportion of the physicochemical data regarding such proteins, it cannot readily account for the alterations on anesthetic effects that are due to mutations within TM4.
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5.
  • Biverståhl, Henrik, 1977- (författare)
  • Structure and Dynamics of Membrane Associated Peptides
  • 2008
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • The peptide-membrane interaction is a key element for many biological functions, from cell signaling to cell internalization. In this thesis the peptide-membrane interaction of six different peptides have been studied with respect to their structure, membrane location and dynamics with spectroscopic methods. Penetratin and the N-terminal sequence of the bovine prion protein (1-30), bPrPp, belong to a class of peptides called cell-penetrating peptides (CPPs). CPPs are short, often highly basic peptides that have the ability to facilitate translocation of an attached hydrophilic cargo over cell-membrane. CD and NMR spectroscopy reveled that penetratin, the (supposedly) non-penetrating mutant pentratin(W48F,W56F) and bPrPp are all highly helical in membrane mimicking media. The position with respect to the bilayer is, however, very different for the three peptides, Penetratin is residing on the membrane surface with a slight tilt while bPrPp is transmembrane and penetratin(W48F,W56F) is somewere in between. These differences can explain the different impact these peptides have on membranesWe have also shown that penetratin can escape from vesicles when an electrochemical or pH gradient is present over the membrane, which support endocytotic internalization.Melittin is a 26 amino acid long residue long peptide and is the major component of the European honey bee venom. Many studies have shown that melittin induces a transient pore that causes leakage in both natural and artificial membranes. In paper IV we used melittin as a model-peptide to investigate how peptides affect lipid dynamics in model-membranes. We showed that carbon-13 relaxation of the lipids could be used to characterize peptide induced changes in lipid dynamicsThe voltage sensor is a domain of the voltage-dependent potassium channel containing several positively charged amino acids (usually arginines). The sensor undergoes a conformational change as a response to a membrane potential. Here, we have studied the membrane location of two fragments corresponding to the “paddle” domain of two different potassium channels, KvAP and HsapBK. NMR and fluorescence studies indicate that both peptides reside inside of the hydrophobic interior of the bilayer, which show that the fragment behave the same way as it does in the intact protein.All six of these peptides interact strongly with model-membranes and adopt a helical conformation even though they have very different biological function. The difference in biological function can instead be explained by the variation in membrane position and membrane dynamics of these peptides
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6.
  • Hugonin, Loïc, 1978- (författare)
  • Spectroscopic studies of dynorphin neuropeptides and the amyloid beta-peptide : The consequences of biomembrane interactions
  • 2007
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • Dynorphin A, dynorphin B and big dynorphin are endogenous opioid neuropeptides. They play an important role in a wide variety of physiological functions such as regulation of pain processing and memory acquisition. Such actions are generally mediated through the κ-receptors. Besides opioid receptor interactions, dynorphins have non-opioid physiological activities which result in excitotoxic effects in neuropathic pain, spinal cord and brain injury. In order to gain insight into the mechanisms of the non-opioid interactions of dynorphins with the cell, spectroscopic membrane-interaction studies were performed. We demonstrated that big dynorphin and dynorphin A, but not dynorphin B, penetrated into cells. All dynorphins interact with the membrane model systems with weak membrane-induced secondary structure. Big dynorphin and dynorphin A induce membrane perturbation, calcein leakage and cause permeability of the membrane to calcium in large unilamellar vesicles (LUV). But dynorphins do not translocate in the LUV membrane model system and there is a strong electrostatic contribution to the interaction of the peptides with the membrane bilayer.In the second part of this thesis we investigated the amyloid β(1-40) peptide (Aβ). This peptide is related to Alzheimer’s disease and its soluble oligomeric aggregates are reported to contribute to the pathology of the disease. In order to provide better insight into the aggregation processes we examined the membrane interaction of Aβ in a model system. Gradual addition of small amounts of sodium dodecyl sulfate to an aqueous solution gives rise to a secondary structure conversion of Aβ peptide. The conversion can be described as a two state process, from random coil to β-sheet with formation of high molecular mass complexes between peptide and detergent, possibly mimicking the behavior of the peptide when aggregating at a cell membrane surface. At high detergent concentrations there is a transition from β-sheet to α-helix conformation.
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7.
  • Lepp, Håkan, 1977- (författare)
  • Experimental studies of proton translocation reactions in biological systems : Electrogenic events in heme-copper oxidases
  • 2008
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • Terminal heme-copper oxidases (HCuOs) are transmembrane proteins that catalyze the final step in the respiratory chain - the reduction of O2 to H2O, coupled to energy conservation by generation of an electrochemical proton gradient. The most extensively investigated of the HCuOs are the aa3-type oxidases, to which cytochrome c oxidase (CytcO) belongs, which uses energy released in the O2-reduction for proton pumping. The bacterial nitric oxide reductases (NORs) have been identified as divergent members of the HCuO-superfamily and are involved in the denitrification pathway where they catalyze the reduction of NO to NO2. Although as exergonic as O2-reduction, this reaction is completely non-electrogenic. Among the traditional HCuOs, the cbb3-type oxidases are the closest relatives to the NORs and as such provide a link between the aa3 oxidases and the NORs. The cbb3 oxidases have been shown to pump protons with nearly the same efficiency as the aa3 oxidases, despite low sequence similarity.This thesis is focused on measurements of membrane potential generating reactions during catalysis in the CytcO and the cbb3 oxidase from Rhodobacter sphaeroides, and the NOR from Paracoccus denitrificans, using a time resolved electrometric technique. The pH dependence of the membrane potential generation in CytcO showed that only one proton is taken up and that no protons are pumped, at high pH. An additional kinetic phase was also detected at high pH that presumably originates to from charge-transfer within the K-pathway. Possible reasons for uncoupling, and the extent of charge-transfer, were studied using structural variants of CytcO. The measurements established that electrons and protons are taken up from the same side of the membrane in NOR. In addition, the directionality for proton uptake in cbb3 oxidase appeared to be dependent on the choice of substrate while proton pumping was indicated to occur only during O2-reduction.
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8.
  • Oglęcka, Kamila, 1977- (författare)
  • Biophysical studies of membrane interacting peptides derived from viral and Prion proteins
  • 2007
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • This thesis focuses on peptides derived from the Prion, Doppel and Influenza haemagglutinin proteins in the context of bilayer interactions with model membranes and live cells. The studies involve spectroscopic techniques like fluorescence, fluorescence correlation spectroscopy (FCS), circular and linear dichroism (CD and LD), confocal fluorescence microscopy and NMR.The peptides derived from the Prion and Doppel proteins combined with their subsequent nuclear localization-like sequences, makes them resemble cell-penetrating peptides (CPPs). mPrPp(1-28), corresponding to the first 28 amino acids of the mouse PrP, was shown to translocate across cell membranes, concomitantly causing cell toxicity. Its bovine counterpart bPrPp(1-30) was demonstrated to enter live cells, with and without cargo, mainly via macropinocytosis. The mPrPp(23-50) peptide sequence overlaps with mPrPp(1-28) sharing the KKRPKP sequence believed to encompass the driving force behind translocation. mPrPp(23-50) was however found unable to cross over cell membranes and had virtually no perturbing effects on membranes.mDplp(1-30), corresponding of the first 30 N-terminal amino acids of the Doppel protein, was demonstrated to be almost as membrane perturbing as melittin. NMR experiments in bicelles implied a transmembrane configuration of its alpha-helix, which was corroborated by LD in vesicle bilayers. The positioning of the induced alpha-helix in transportan was found to be more parallel to the bilayer surface in the same model system.Positioning of the native Influenza derived fusion peptide in bilayers showed no pH dependence. The glutamic acid enriched variant however, changed its insertion angle from 70 deg to a magic angle alignment relative the membrane normal upon a pH drop from 7.4 to 5.0. Concomitantly, the alpha-helical content dramatically rose from 18% to 52% in partly anionic membranes, while the native peptide’s helicity increased only from 39% to 44% in the same conditions.
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9.
  • Papadopoulos, Evangelos, 1975- (författare)
  • Structural and functional studies of biomolecules with NMR and CD spectroscopy.
  • 2008
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • Experimentally derived biomolecular structures were determined by Nuclear Magnetic Resonance (NMR). The properties of selected peptides and proteins in solution and in membrane mimicking micelles were observed by circular Dichroism (CD), mass spectrometry (MS), and other spectroscopic techniques.The mDpl(1-30) peptide (30 residues) of the mouse Doppel protein was found to be positioned as an α-helix in a DHPC micelle. The same peptide can disrupt and cause leakage in small unilamellar vesicles.Single D-amino acid isomers of Trp-cage (20 residues), the smallest peptide with a protein-like fold, were analyzed by CD spectroscopy and were found to have different secondary structures and melting temperatures. They were compared against MS measurements specially designed to reveal the secondary structure of proteins.We studied a novel protein in E. coli of unknown structure that is encoded by the putative transcription factor ORF: ygiT (131 residues). This protein comprises a helix-turn-helix (HTH) domain in the C-terminus and contains two CxxC motives in the N-terminal domain, which binds Zn. This protein was named 2CxxC. We succeeded in overexpressing and purifying 2CxxC in E. coli with enough yield for a 13C, 15N uniformly labeled NMR sample. The chemical shift assignment was completed and the NMR structure was calculated in reducing, slightly acidic conditions (1mM DTT, pH 5.5). The determined HTH domain shows good similarity with structures predicted by a homology search, while the N-terminal domain has no other homologous structure in the Protein Data Bank (PDB).The structure of the paddle region (27 residues) of the HsapBK(233-260) voltage and Ca+2 activated potassium channel, in DPC micelles, was determined by NMR. It shows a helix-turn-helix loop, which agrees well with the expected structure and could help to verify the proposed models of the voltage gating mechanism.The C-repressor (dimer of 99 residues) of bacteriophage P2 was analyzed by NMR. We assigned the chemical shifts and NMR structure determination is under way.
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