Molecular dynamics simulations and free energy calculations on the enzyme 4‐hydroxyphenylpyruvate dioxygenase

4‐Hydroxyphenylpyruvate dioxygenase is a relevant target in both pharmaceutical and agricultural research. We report on molecular dynamics simulations and free energy calculations on this enzyme, in complex with 12 inhibitors for which experimental affinities were determined. We applied the thermodynamic integration approach and the more efficient one‐step perturbation. Even though simulations seem well converged and both methods show excellent agreement between them, the correlation with the experimental values remains poor. We investigate the effect of slight modifications on the charge distribution of these highly conjugated systems and find that accurate models can be obtained when using improved force field parameters. This study gives insight into the applicability of free energy methods and current limitations in force field parameterization. © 2011 Wiley Periodicals, Inc. J Comput Chem 2011

[1]  J. Kirkwood.  Statistical Mechanics of Fluid Mixtures , 1935 .

[2]  R. Zwanzig.  High‐Temperature Equation of State by a Perturbation Method. I. Nonpolar Gases , 1954 .

[3]  Irwin Oppenheim,et al.  Statistical Mechanical Theory of Transport Processes. VII. The Coefficient of Thermal Conductivity of Monatomic Liquids , 1954 .

[4]  Y. Cheng,et al.  Relationship between the inhibition constant (K1) and the concentration of inhibitor which causes 50 per cent inhibition (I50) of an enzymatic reaction. , 1973, Biochemical pharmacology.

[5]  G. Ciccotti,et al.  Numerical Integration of the Cartesian Equations of Motion of a System with Constraints: Molecular Dynamics of n-Alkanes , 1977 .

[6]  H. Berendsen,et al.  Interaction Models for Water in Relation to Protein Hydration , 1981 .

[7]  James Andrew McCammon,et al.  Ligand-receptor interactions , 1984, Comput. Chem..

[8]  H. Berendsen,et al.  Molecular dynamics with coupling to an external bath , 1984 .

[9]  D. Beveridge,et al.  Free energy via molecular simulation: applications to chemical and biomolecular systems. , 1989, Annual review of biophysics and biophysical chemistry.

[10]  Johan Åqvist,et al.  Modelling of ion-ligand interactions in solutions and biomolecules , 1992 .

[11]  S. Lindstedt,et al.  Treatment of hereditary tyrosinaemia type I by inhibition of 4-hydroxyphenylpyruvate dioxygenase , 1992, The Lancet.

[12]  A. Schulz,et al.  SC‐0051, a 2‐benzoyl‐cyclohexane‐1,3‐dione bleaching herbicide, is a potent inhibitor of the enzyme p‐hydroxyphenylpyruvate dioxygenase , 1993, FEBS letters.

[13]  Peter A. Kollman,et al.  FREE ENERGY CALCULATIONS : APPLICATIONS TO CHEMICAL AND BIOCHEMICAL PHENOMENA , 1993 .

[14]  J. Aqvist,et al.  A new method for predicting binding affinity in computer-aided drug design. , 1994, Protein engineering.

[15]  A. Mark,et al.  Avoiding singularities and numerical instabilities in free energy calculations based on molecular simulations , 1994 .

[16]  Jonathan W. Essex,et al.  Generalized alteration of structure and parameters: A new method for free‐energy perturbations in systems containing flexible degrees of freedom , 1995, J. Comput. Chem..

[17]  Wilfred F. van Gunsteren,et al.  A generalized reaction field method for molecular dynamics simulations , 1995 .

[18]  Alan E. Mark,et al.  Estimating the Relative Free Energy of Different Molecular States with Respect to a Single Reference State , 1996 .

[19]  Alan E. Mark,et al.  The GROMOS96 Manual and User Guide , 1996 .

[20]  Thomas D. Y. Chung,et al.  A Simple Statistical Parameter for Use in Evaluation and Validation of High Throughput Screening Assays , 1999, Journal of biomolecular screening.

[21]  Heiko Schäfer,et al.  Estimating relative free energies from a single ensemble: Hydration free energies , 1999 .

[22]  P. Kollman,et al.  Calculating structures and free energies of complex molecules: combining molecular mechanics and continuum models. , 2000, Accounts of chemical research.

[23]  M. Erion,et al.  Calculation of relative binding free energy differences for fructose 1,6-bisphosphatase inhibitors using the thermodynamic cycle perturbation approach. , 2001, Journal of the American Chemical Society.

[24]  Mark A. Miller,et al.  Why is it so difficult to simulate entropies, free energies, and their differences? , 2001, Accounts of chemical research.

[25]  J. Åqvist,et al.  Ligand binding affinities from MD simulations. , 2002, Accounts of chemical research.

[26]  M. J. Ryle,et al.  Non-heme iron oxygenases. , 2002, Current opinion in chemical biology.

[27]  Martin Almlöf,et al.  Free energy calculations and ligand binding. , 2003, Advances in protein chemistry.

[28]  Michael R. Shirts,et al.  Extremely precise free energy calculations of amino acid side chain analogs: Comparison of common molecular mechanics force fields for proteins , 2003 .

[29]  Wilfred F van Gunsteren,et al.  Free energies of binding of polychlorinated biphenyls to the estrogen receptor from a single simulation , 2003, Proteins.

[30]  S. Steinbacher,et al.  The Crystal Structures of Zea mays and Arabidopsis 4-Hydroxyphenylpyruvate Dioxygenase , 2004, Plant Physiology.

[31]  Chris Oostenbrink,et al.  A biomolecular force field based on the free enthalpy of hydration and solvation: The GROMOS force‐field parameter sets 53A5 and 53A6 , 2004, J. Comput. Chem..

[32]  E. Lock,et al.  From toxicological problem to therapeutic use: The discovery of the mode of action of 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC), its toxicology and development as a drug , 1998, Journal of Inherited Metabolic Disease.

[33]  Cheng Yang,et al.  Structural basis for herbicidal inhibitor selectivity revealed by comparison of crystal structures of plant and mammalian 4-hydroxyphenylpyruvate dioxygenases. , 2004, Biochemistry.

[34]  Markus Christen,et al.  The GROMOS software for biomolecular simulation: GROMOS05 , 2005, J. Comput. Chem..

[35]  G. Moran.  4-Hydroxyphenylpyruvate dioxygenase. , 2005, Archives of biochemistry and biophysics.

[36]  N. Foloppe,et al.  Towards predictive ligand design with free-energy based computational methods? , 2006, Current medicinal chemistry.

[37]  Wilfred F van Gunsteren,et al.  Biomolecular modeling: Goals, problems, perspectives. , 2006, Angewandte Chemie.

[38]  Wilfred F van Gunsteren,et al.  Sampling of rare events using hidden restraints. , 2006, The journal of physical chemistry. B.

[39]  William L. Jorgensen,et al.  FEP-guided selection of bicyclic heterocycles in lead optimization for non-nucleoside inhibitors of HIV-1 reverse transcriptase. , 2006 .

[40]  Niu Huang,et al.  Physics-based methods for studying protein-ligand interactions. , 2007, Current opinion in drug discovery & development.

[41]  David L Mobley,et al.  The Confine-and-Release Method: Obtaining Correct Binding Free Energies in the Presence of Protein Conformational Change. , 2007, Journal of chemical theory and computation.

[42]  R. Beaudegnies,et al.  Herbicidal 4-hydroxyphenylpyruvate dioxygenase inhibitors--a review of the triketone chemistry story from a Syngenta perspective. , 2009, Bioorganic & medicinal chemistry.

[43]  M. Witschel.  Design, synthesis and herbicidal activity of new iron chelating motifs for HPPD-inhibitors. , 2009, Bioorganic & medicinal chemistry.

[44]  Kenneth M Merz,et al.  Limits of Free Energy Computation for Protein-Ligand Interactions. , 2010, Journal of chemical theory and computation.

[45]  Arieh Warshel,et al.  A comprehensive examination of the contributions to the binding entropy of protein–ligand complexes , 2010, Proteins.

[46]  Francesca Perruccio,et al.  HPPD: Ligand- and Target-Based Virtual Screening on a Herbicide Target , 2010, J. Chem. Inf. Model..

[47]  Jozef Hritz,et al.  Calculations of binding affinity between C8-substituted GTP analogs and the bacterial cell-division protein FtsZ , 2010, European Biophysics Journal.