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  • 1.
    Sevastik, Robin
    KTH, School of Biotechnology (BIO), Theoretical Chemistry.
    Quantum chemical modeling of enzymatic reactions: applications to the tautomerase superfamily2008Licentiate thesis, comprehensive summary (Other scientific)
    Abstract [en]

    In this thesis, quantum chemical methods are used to investigate enzymatic reaction mechanisms. The Density functional theory, in particular the hybrid B3LYP functional, is used to model two enzymes belonging to the tautomerase superfamily; 4-Oxalocrotonate Tautomerase (4-OT) and cis-Chloroacrylic Acid Dehalogenase (cis-CAAD). The methodology is presented and new mechanistic insights for the two enzymes are discussed.

    For 4-OT, two different models are built and the potential energy curves are computed. This allows the methodology to be evaluated. The results give new insight into the energetics of the 4-OT reaction, indicating that the charge-separated intermediate is quite close in energy to the reactant species. The models also make it possible to perform in silico mutations to investigate the role of active site groups. Excellent agreement is found between the calculations and site-directed mutagenesis experiments, further substantiating the validity of the models.

    For cis-CAAD, the uncatalyzed reaction is first considered and excellent agreement is found between the calculated barrier and the measured rate constant. The enzymatic reaction is then studied with a quite large active site model and a reaction mechanism is proposed.

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  • 2.
    Sevastik, Robin
    et al.
    KTH, School of Biotechnology (BIO), Theoretical Chemistry.
    Himo, Fahmi
    KTH, School of Biotechnology (BIO), Theoretical Chemistry.
    Quantum chemical modeling of enzymatic reactions: the case of 4-oxalocrotonate tautomerase2007In: Bioorganic chemistry (Print), ISSN 0045-2068, Vol. 35, no 6, p. 444-457Article in journal (Refereed)
    Abstract [en]

    The reaction mechanism of 4-oxalocrotonate tautomerase (4-OT) is studied using the density functional theory method B3LYP. This enzyme catalyzes the isomerisation of unconjugated alpha-keto acids to their conjugated isomers. Two different quantum chemical models of the active site are devised and the potential energy curves for the reaction are computed. The calculations support the proposed reaction mechanism in which Pro-1 acts as a base to shuttle a proton from the C3 to the C5 position of the substrate. The first step (proton transfer from C3 to proline) is shown to be the rate-limiting step. The energy of the charge-separated intermediate (protonated proline-deprotonated substrate) is calculated to be quite low, in accordance with measured pK(a) values. The results of the two models are used to evaluate the methodology employed in modeling enzyme active sites using quantum chemical cluster models.

  • 3.
    Sevastik, Robin
    et al.
    KTH, School of Biotechnology (BIO), Theoretical Chemistry.
    Himo, Fahmi
    KTH, School of Biotechnology (BIO), Theoretical Chemistry.
    Reaction mechanism of cis-chloroacrylic acid dehalogenase: a theoretical studyManuscript (Other academic)
  • 4.
    Sevastik, Robin
    et al.
    Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University.
    Whitman, Christian P.
    Division of Medicinal Chemistry, College of Pharmacy, University of Texas.
    Himo, Fahmi
    Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University.
    Reaction Mechanism of cis-3-Chloroacrylic Acid Dehalogenase: A Theoretical Study2009In: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 48, no 40, p. 9641-9649Article in journal (Refereed)
    Abstract [en]

    The reaction mechanism of cis-3-chloroacrylic acid dehalogenase (cis-CaaD) is studied using the B3LYP density functional theory method. This enzyme catalyzes the hydrolytic dehalogenation of cis-3-chloroacrylic acid to yield malonate semialdehyde and HCl. The uncatalyzed reaction is first considered, and excellent agreement is found between the calculated barrier and the measured rate constant. The enzymatic reaction is then studied with an active site model consisting of 159 atoms. The results suggest an alternative mechanism for cis-CaaD catalysis and different roles for some active site residues in this mechanism.

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