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  • 1.
    Gustafsson, Camilla
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Theoretical Chemistry and Biology. KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Chemistry, Applied Physical Chemistry. KTH, Royal Institute of Technology.
    Modeling environment effects on spectroscopic properties of biomarkers and catalytic mechanisms in enzymes2020Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Arguably, humans are in need of both better diagnostic tools to prevent pro- gression of diseases as well as greener catalysts for synthesis of chemicals.

    Neurodegenerative diseases affecting neurons in the brain leads to demen- tias, where Alzheimer’s disease (AD) is the most prevalent. It is estimated that about 50 million people worldwide suffer from AD, a number that has more than doubled during the last 30 years. Currently, there is no cure for AD, but in order to slow the progression of symptoms it is crucial to develop biomarkers for early detection and initiation of clinical interventions.

    With theoretical tools it is possible to better understand the optical prop- erties of fluorescent biomarkers, and thus contribute to steering the design of biomarkers for distinguishing different types of disease-associated proteins. Lu- minescent conjugated oligothiophenes (LCO) is a class of molecules that binds to aggregates of misfolded amyloid-β proteins, facilitating in vivo-detection of the pathological hallmarks of AD. By performing molecular dynamics (MD) simulations and subsequent response theory calculations of a LCO, it could be concluded that the differences in the spectroscopic fingerprints for the bound and free biomarker were predominantly due to conformational changes of the conjugated π-system in the molecular backbone. The introduction of differ- ent central units with donor properties yield donor-acceptor-donor electronic systems that increase the range of spectroscopic detection of LCO biomark- ers, without reducing the selectivity towards amyloid-β. It was also revealed that in order to capture more of the two-photon absorption (TPA) signal it would be optimal to design biomarkers with the dominant TPA signal at longer wavelenghts.

    The second part of this work is centered around computational enzyme design, and how single point mutations can alter the flow of water in the active site. The altered flow of water likely impacts the catalysis in the active site of the enzymes. The enzymes considered in this work belongs to two different enzyme classes, and catalyse different kinds of reactions. Squalene hopene cyclase (SHC) is a monotopic membrane enzyme that catalyses the cyclization of squalene to hopene, and ω-transaminase catalyses the transfer of an amino and keto group between an amino acid and a keto acid. Enzyme variants of both SHC and ω-transaminase, where single-point mutations have been introduced, display different experimentally observed properties compared to their corresponding wild-types (WT). By performing MD simulations, the flow of water in the active sites of both enzymes could be tracked. Distinct differences in the flow of water in the WT and enzyme variants could be detected. These changes are proposed to influence the catalysis, and help to explain the experimentally observed differences in the protein variants.

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  • 2.
    Gustafsson, Camilla
    et al.
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Theoretical Chemistry and Biology.
    Linares, Mathieu
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Theoretical Chemistry and Biology.
    Norman, Patrick
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Theoretical Chemistry and Biology.
    Quantum Mechanics/Molecular Mechanics Density Functional Theory Simulations of the Optical Properties Fingerprinting the Ligand-Binding of Pentameric Formyl Thiophene Acetic Acid in Annyloid-beta(1-42)2020In: Journal of Physical Chemistry A, ISSN 1089-5639, E-ISSN 1520-5215, Vol. 124, no 5, p. 875-888Article in journal (Refereed)
    Abstract [en]

    The binding pocket proposed by Konig et al. [Chem. Commun. 2018, 54, 3030-3033] for the biomarker pentameric formyl thiophene acetic acid (p-FTAA) in the fibrillar structure of amyloid-beta(1-42) has been put to the test by the comparison of theoretical and experimental optical absorption and fluorescence spectra obtained in a water environment and inside the protein scaffold. The optical absorption/emission properties of this luminescent conjugated oligothiophene were studied by means of classical force field molecular dynamics simulations to account for the sampling of configuration space in conjunction with polarizable embedding time-dependent density functional theory calculations of spectra. The nuclear motions of residues in the beta-sheet were found to be modest, and the time dependence of embedding parameters was shown to be negligible so that a time-independent parameter set could be derived and used for all 300 snapshots considered in the spectrum averaging. In regard to linear absorption spectra, the calculated red shift due to protein binding for the dominant S-1 <- S-0 transition in p-FTAA was found to be equal to 23 nm (0.17 eV), which is in excellent agreement with the corresponding experimental result of 18 nm and taken as corroborating evidence for having correctly identified the binding pocket of p-FTAA in the amyloid. The underlying mechanisms for the calculated red shift were disentangled, and it is shown that some 20 nm (0.15 eV) of the total 23 nm (0.17 eV) is associated with increased planarity of p-FTAA in the binding pocket, whereas a mere 3 nm (0.02 eV) is associated with changes in the environment. In regard to emission spectra, we demonstrate that intersystem crossing from the excited S-1 state to the triplet manifold of states is a less likely event for p-FTAA in the binding pocket as compared to in the aqueous solution, and we thereby partly explain the much higher quantum yield of fluorescence for the more rigid p-FTAA in the binding pocket. Two-photon absorption in p-FTAA is shown to predominantly occur to an overall symmetric excited state and be more than twice as strong for the biomarker in the binding pocket as compared to in water. The corresponding red shift, on the other hand, is very small. Earlier experimental two-photon fluorescence imaging using p-FTAA is shown not to target the dominant two-photon state, and ways to reach a higher image quality (lower signal-to-noise ratio) are proposed in terms of tuning the laser wavelength toward the region of 600 nm or the synthesis of asymmetric ligands with S-1 states that are both one- and two-photon allowed.

  • 3.
    Gustafsson, Camilla
    et al.
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Chemistry, Applied Physical Chemistry.
    Vassiliev, Serguei
    Department of Biological Sciences, Brock University, Ontario, Canada.
    Kürten, Charlotte
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Syrén, Per-Olof
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Brinck, Tore
    MD Simulations Reveal Complex Water Paths in Squalene–Hopene Cyclase: Tunnel-Obstructing Mutations Increase the Flow of Water in the Active Site2017In: ACS Omega, ISSN 2470-1343, Vol. 2, no 11, p. 8495-8506Article in journal (Refereed)
    Abstract [en]

    Squalene–hopene cyclase catalyzes the cyclization of squalene to hopanoids. A previous study has identified a network of tunnels in the protein, where water molecules have been indicated to move. Blocking these tunnels by site-directed mutagenesis was found to change the activation entropy of the catalytic reaction from positive to negative with a concomitant lowering of the activation enthalpy. As a consequence, some variants are faster and others are slower than the wild type (wt) in vitro under optimal reaction conditions for the wt. In this study, molecular dynamics (MD) simulations have been performed for the wt and the variants to investigate how the mutations affect the protein structure and the water flow in the enzyme, hypothetically influencing the activation parameters. Interestingly, the tunnel-obstructing variants are associated with an increased flow of water in the active site, particularly close to the catalytic residue Asp376. MD simulations with the substrate present in the active site indicate that the distance for the rate-determining proton transfer between Asp376 and the substrate is longer in the tunnel-obstructing protein variants than in the wt. On the basis of the previous experimental results and the current MD results, we propose that the tunnel-obstructing variants, at least partly, could operate by a different catalytic mechanism, where the proton transfer may have contributions from a Grotthuss-like mechanism.

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    MD Simulations Reveal Complex Water Paths in Squalene–Hopene Cyclase: Tunnel-Obstructing Mutations Increase the Flow of Water in the Active Site
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