Dynamics of an enzymatic substitution reaction in haloalkane dehalogenase.

Department of Chemistry and Supercomputing Institute, Digital Technology Center, University of Minnesota, Minneapolis, Minnesota 55455, USA.
Journal of the American Chemical Society (Impact Factor: 10.68). 03/2004; 126(5):1369-76. DOI: 10.1021/ja039093l
Source: PubMed

ABSTRACT Reactive flux molecular dynamics simulations have been carried out using a combined QM/MM potential to study the dynamics of the nucleophilic substitution reaction of dichloroethane by a carboxylate group in haloalkane dehalogenase and in water. We found that protein dynamics accelerates the reaction rate by a factor of 2 over the uncatalyzed reaction. Compared to the thermodynamic effect in barrier reduction, protein dynamic contribution is relatively small. However, analyses of the friction kernel reveal that the origins of the reaction dynamics in water and in the enzyme are different. In aqueous solution, there is significant electrostatic solvation effect, which is reflected by the slow reorganization relaxation of the solvent. On the other hand, there is no strong electrostatic coupling in the enzyme and the major effect on reaction coordinate motion is intramolecular energy relaxation.

  • [Show abstract] [Hide abstract]
    ABSTRACT: A theoretical study of the temperature dependence of dynamic effects in the rate limiting step of the reaction catalyzed by thymidylate synthase is presented in this paper. From hybrid Quantum Mechanics/Molecular Mechanics (QM/MM) optimizations of transition state structures within a fully flexible molecular model, free downhill molecular dynamics trajectories have been performed at four different temperatures. The analysis of the reactive and non-reactive trajectories in the enzyme environment has allowed us to study the geometric and electronic coupling between the substrate, the cofactor and the protein. The results show how the contribution of dynamic effects to the rate enhancement measured by the transmission coefficients is, at the four studied temperatures, negligible. Nevertheless, the rare event trajectories performed have shown how the hydride transfer and the scission of the conserved active site cysteine residue (Cys146 in E. coli) take place in a concerted but asynchronous way; the latter takes place once the transfer has occurred. The analysis of the dynamics of the protein reveals also how the relative movements of some amino acids, especially Arg166, and a water molecule, promotes the departure of the Cys146 from the dUMP. Finally, it seems that the protein environment creates an almost invariant electric field in the active site of the protein that stabilizes the transition state of the reaction, thus reducing the free energy barrier.
    Physical Chemistry Chemical Physics 10/2010; 12(37):11657-64. · 4.20 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Thirty years after the seminal contribution by Warshel and Levitt, we review the state of the art of combined quantum-mechanics/molecular-mechanics (QM/MM) methods, with afocus on biomolecular systems. We provide adetailed overview of the methodology of QM/MM calculations and their use within optimization and simulation schemes. Atabular survey of recent applications, mostly to enzymatic reactions, is given.
    11/2006: pages 173-290;
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Determining the free energies and mechanisms of chemical reactions in solution and enzymes is a major challenge. For such complex reaction processes, combined quantum mechanics/molecular mechanics (QM/MM) method is the most effective simulation method to provide an accurate and efficient theoretical description of the molecular system. The computational costs of ab initio QM methods, however, have limited the application of ab initio QM/MM methods. Recent advances in ab initio QM/MM methods allowed the accurate simulation of the free energies for reactions in solution and in enzymes and thus paved the way for broader application of the ab initio QM/MM methods. We review here the theoretical developments and applications of the ab initio QM/MM methods, focusing on the determination of reaction path and the free energies of the reaction processes in solution and enzymes.
    Journal of Molecular Structure THEOCHEM 03/2009; 898(1-3):17-30. · 1.37 Impact Factor


Available from