Computational modeling of enzymatic keto-enol isomerization reactions

  title={Computational modeling of enzymatic keto-enol isomerization reactions},
  author={Isabella Feierberg and Johan {\AA}qvist},
  journal={Theoretical Chemistry Accounts},
Abstract. Catalysis of proton abstraction from nonacidic carbon atoms adjacent to a carbonyl or carboxylate group is a fundamental reaction in enzymology that has been extensively studied during the last few decades. Enzymes catalyzing these reactions, which normally involve labile enolic intermediates, need to overcome large pKa differences between the reacting groups as well as high intrinsic free-energy barriers. Here, we present an overview of results from recent computer simulation studies… 
Theoretical study of enzymatically catalyzed tautomerization of carbon acids in aqueous solution: quantum calculations and steered molecular dynamics simulations
The thermodynamics and kinetics of enzymatically assisted reactions of carbon acids were studied theoretically and simulations of these reactions were qualitatively consistent with the values obtained using QE as well as those found by other authors in similar studies.
Using Unnatural Amino Acids to Probe the Energetics of Oxyanion Hole Hydrogen Bonds in the Ketosteroid Isomerase Active Site
The observed shallow dependence of activity on the pKa of the substituted Tyr residues suggests that the KSI oxyanion hole does not provide catalysis by forming an energetically exceptional pKa-matched hydrogen bond, consistent with prior experimental results.
Impact of mutation on proton transfer reactions in ketosteroid isomerase: insights from molecular dynamics simulations.
Calculated rate constants suggest that KSI forms a preorganized active site but that the structure of this pre organized active site is altered upon mutation, and small conformational changes due to stochastic thermal motions are required within this preorganizedactive site to facilitate the proton transfer reactions.
Hydrogen bonding in the active site of ketosteroid isomerase: electronic inductive effects and hydrogen bond coupling.
Computational studies are performed to analyze the physical properties of hydrogen bonds donated by Tyr16 and Asp103 to a series of substituted phenolate inhibitors bound in the active site of ketosteroid isomerase, and suggest that the differences in the experimental NMR data and electronic absorption spectra for pKSI and tKSI, two homologous bacterial forms of the enzyme, are due predominantly to the third tyrosine.
Optimal alignment for enzymatic proton transfer: Structure of the Michaelis complex of triosephosphate isomerase at 1.2-Å resolution
This work focuses on the initial proton transfer of the isomerization reaction catalyzed by triosephosphate isomerase and presents the crystal structure of its Michaelis complex with the substrate dihydroxyacetone phosphate at near-atomic resolution.
Atomic resolution crystallography of a complex of triosephosphate isomerase with a reaction‐intermediate analog: New insight in the proton transfer reaction mechanism
The structure analysis suggests that the hydroxamate moiety of PGH is negatively charged, and the bound PGH mimics the negatively charged enediolate intermediate, which is formed immediately after the initial proton abstraction from DHAP by the catalytic glutamate.
Triosephosphate isomerase: a highly evolved biocatalyst
Two proton shuttling mechanisms, the classical and the criss-cross mechanism, are responsible for the interconversion of the substrates of this enolising enzyme.
Hybrid quantum/classical molecular dynamics simulations of the proton transfer reactions catalyzed by ketosteroid isomerase: analysis of hydrogen bonding, conformational motions, and electrostatics.
The results suggest that relatively small conformational changes of the enzyme active site and substrate strengthen the hydrogen bonds that stabilize the intermediate, thereby facilitating the proton transfer reactions.
Mechanism of peptide bond synthesis on the ribosome.
  • Stefan Trobro, J. Åqvist
  • Chemistry, Medicine
    Proceedings of the National Academy of Sciences of the United States of America
  • 2005
The observed H-bond network suggests an important structural role of several universally conserved rRNA residues, and the catalytic effect is found to be entirely of entropic origin, in accordance with recent experimental data.
Folding-Reaction Coupling in a Self-Cleaving Protein.
There is strong coupling between folding and reaction coordinates leading to reactant state destabilization in the direction of folding and transition state stabilization along the reaction coordinate, and a quantitative estimate of the free energy stored as protein strain is obtained.


Computer Modeling of Chemical Reactions in Enzymes and Solutions
Basic Principles of Chemical Bonding. Chemical Reactions in the Gas Phase and in Simple Solvent Models. Chemical Reaction in All--Atom Solvent Models. Potential Surfaces and Simulations of