COMPUTER SIMULATION OF ENZYMATIC REACTIONS

Summary

Principal Investigator: A Warshel
Affiliation: University of Southern California
Country: USA
Abstract: Gaining a quantitative description of enzyme action is one of the most important challenges of molecular biology. Thus, we propose a continuation of our research projects aimed at the development, refinement, and implementation of computational models for simulations of enzymatic reactions. During previous grant periods we have demonstrated the general applicability of our empirical valence bond (EVB) approach. In recent years we started to develop more rigorous ab initio approaches that exploit the increasing availability of computer power. Our new strategies include: (a) quantum mechanical (ab initio)/Langevin dipole (QM(ai)/LD) model which provide crucial information about potential surfaces of reactions in solution. This allows us to calibrate EVB surfaces for studies of enzymes; (b) an ab initio free energy perturbation (QM(ai)/FEP) which uses EVB surfaces as reference potentials and thus allows us to start evaluating ab initio free energies of enzymatic reactions; and (c) a constrain density functional theory (CDFT) approach, which allows us to represent large parts of the protein at the ab initio level. Although these approaches still require further validation, we are ready to use them in studies of enzymatic catalysis. In addition to the method development projects, we have made significant progress in studying different classes of enzymatic reactions and in exploring the feasibility of different catalytic mechanisms. In order to exploit our advanced we propose to advance in the following three directions: (a) we will conduct method development studies that will include: (i) improving our ab initio approaches for constructing reference solution reactions. In particular, we will focus on transition state search and evaluation of entropic corrections for solution reactions; (ii) using solution surfaces in automated refined of EVB surfaces; (iii) using the EVB surfaces as reference potentials in automated refinement of EVB surfaces; (iii) using the EVB surfaces as reference potentials for QM(ai)/FEP studies of enzymes; (iv) CDFT studies of metalloenzyme. (b) We will conduct systematic studies of several important classes of enzymatic reactions including: (i) serine and cysteine proteases; (ii) DNA polymerase; and (iii) ribonuclease. (c) We will conduct studies of the relative importance of different catalytic proposals, including (i) entropic effects; (ii) low barrier hydrogen bond; (iii) near attack conformers; and (iv) pre-organization of enzyme active sites.
Funding Period: 1978-01-01 - 2006-03-31
more information: NIH RePORT

Top Publications

  1. pmc Computer simulations of protein functions: searching for the molecular origin of the replication fidelity of DNA polymerases
    Jan Florian
    Department of Chemistry, Loyola University, Chicago, IL 60626, USA
    Proc Natl Acad Sci U S A 102:6819-24. 2005
  2. ncbi Simulation of tunneling in enzyme catalysis by combining a biased propagation approach and the quantum classical path method: application to lipoxygenase
    Janez Mavri
    National Institute of Chemistry, Hajdrihova 19, 1000 Ljubljana, Slovenia
    J Phys Chem B 112:5950-4. 2008
  3. doi Quantifying free energy profiles of proton transfer reactions in solution and proteins by using a diabatic FDFT mapping
    Yun Xiang
    Department of Chemistry, University of Southern California, 3620 McClintock Avenue, Los Angeles, California 90089 1062, USA
    J Phys Chem B 112:1007-15. 2008
  4. pmc Accelerating QM/MM free energy calculations: representing the surroundings by an updated mean charge distribution
    Edina Rosta
    Department of Chemistry, University of Southern California, 418 SGM Building, 3620 McClintock Avenue, Los Angeles, California 90089 1062, USA
    J Phys Chem B 112:5680-92. 2008
  5. pmc Solvation free energies of molecules. The most stable anionic tautomers of uracil
    Maciej Haranczyk
    Department of Chemistry, University of Southern California, 418 SGM Building, 3620 McClintock Avenue, Los Angeles, CA 90089 1062, USA
    Phys Chem Chem Phys 10:4442-8. 2008
  6. pmc On the relationship between folding and chemical landscapes in enzyme catalysis
    Maite Roca
    Department of Chemistry, University of Southern California, 418 SGM Building, 3620 McClintock Avenue, Los Angeles, CA, 90089 1062, USA
    Proc Natl Acad Sci U S A 105:13877-82. 2008
  7. pmc Progress in ab initio QM/MM free-energy simulations of electrostatic energies in proteins: accelerated QM/MM studies of pKa, redox reactions and solvation free energies
    Shina C L Kamerlin
    Department of Chemistry, University of Southern California, 418 SGM Building, 3620 McClintock Avenue, Los Angeles, California 90089 1062, USA
    J Phys Chem B 113:1253-72. 2009
  8. pmc Toward accurate screening in computer-aided enzyme design
    Maite Roca
    Department of Chemistry, University of Southern California, Los Angeles, California 90089 1062, USA
    Biochemistry 48:3046-56. 2009
  9. pmc The empirical valence bond as an effective strategy for computer-aided enzyme design
    Alexandra Vardi-Kilshtain
    Department of Chemistry, University of Southern California, Los Angeles, USA
    Biotechnol J 4:495-500. 2009
  10. pmc On the origin of the catalytic power of carboxypeptidase A and other metalloenzymes
    Alexandra Vardi Kilshtain
    Department of Chemistry, University of Southern California, Los Angeles, California 90089 1062, USA
    Proteins 77:536-50. 2009

Scientific Experts

Detail Information

Publications27

  1. pmc Computer simulations of protein functions: searching for the molecular origin of the replication fidelity of DNA polymerases
    Jan Florian
    Department of Chemistry, Loyola University, Chicago, IL 60626, USA
    Proc Natl Acad Sci U S A 102:6819-24. 2005
    ..The calculations demonstrate the potential for further integration of theoretical and experimental studies to analyze high- and low-fidelity DNA polymerases...
  2. ncbi Simulation of tunneling in enzyme catalysis by combining a biased propagation approach and the quantum classical path method: application to lipoxygenase
    Janez Mavri
    National Institute of Chemistry, Hajdrihova 19, 1000 Ljubljana, Slovenia
    J Phys Chem B 112:5950-4. 2008
    ..In particular, this approach can be used to evaluate the quantum mechanical transmission factor or other dynamical effects, while still obtaining reliable quantized activation free energies due to the QCP correction...
  3. doi Quantifying free energy profiles of proton transfer reactions in solution and proteins by using a diabatic FDFT mapping
    Yun Xiang
    Department of Chemistry, University of Southern California, 3620 McClintock Avenue, Los Angeles, California 90089 1062, USA
    J Phys Chem B 112:1007-15. 2008
    ..Our results point out that the present implementation of the FDFT approach provides a very promising approach for evaluating QM(ai)/MM free energy surfaces...
  4. pmc Accelerating QM/MM free energy calculations: representing the surroundings by an updated mean charge distribution
    Edina Rosta
    Department of Chemistry, University of Southern California, 418 SGM Building, 3620 McClintock Avenue, Los Angeles, California 90089 1062, USA
    J Phys Chem B 112:5680-92. 2008
    ..This approach should provide a very powerful tool for QM(ai)/MM evaluation of solvation free energies in aqueous solutions and proteins...
  5. pmc Solvation free energies of molecules. The most stable anionic tautomers of uracil
    Maciej Haranczyk
    Department of Chemistry, University of Southern California, 418 SGM Building, 3620 McClintock Avenue, Los Angeles, CA 90089 1062, USA
    Phys Chem Chem Phys 10:4442-8. 2008
    ..We found that in water solution three of the recently identified anionic tautomers are 6.5-3.6 kcal mol(-1) more stable than the anion of the canonical tautomer...
  6. pmc On the relationship between folding and chemical landscapes in enzyme catalysis
    Maite Roca
    Department of Chemistry, University of Southern California, 418 SGM Building, 3620 McClintock Avenue, Los Angeles, CA, 90089 1062, USA
    Proc Natl Acad Sci U S A 105:13877-82. 2008
    ..This work provides insight into the relationship between folding landscapes and catalysis. The computational approach used here may also provide a powerful strategy for modeling single-molecule experiments and designing enzymes...
  7. pmc Progress in ab initio QM/MM free-energy simulations of electrostatic energies in proteins: accelerated QM/MM studies of pKa, redox reactions and solvation free energies
    Shina C L Kamerlin
    Department of Chemistry, University of Southern California, 418 SGM Building, 3620 McClintock Avenue, Los Angeles, California 90089 1062, USA
    J Phys Chem B 113:1253-72. 2009
    ....
  8. pmc Toward accurate screening in computer-aided enzyme design
    Maite Roca
    Department of Chemistry, University of Southern California, Los Angeles, California 90089 1062, USA
    Biochemistry 48:3046-56. 2009
    ....
  9. pmc The empirical valence bond as an effective strategy for computer-aided enzyme design
    Alexandra Vardi-Kilshtain
    Department of Chemistry, University of Southern California, Los Angeles, USA
    Biotechnol J 4:495-500. 2009
    ..The ability of the model to predict quantitatively the catalytic power of enzymes should augment the capacity of current approaches for enzyme design...
  10. pmc On the origin of the catalytic power of carboxypeptidase A and other metalloenzymes
    Alexandra Vardi Kilshtain
    Department of Chemistry, University of Southern California, Los Angeles, California 90089 1062, USA
    Proteins 77:536-50. 2009
    ..This and earlier studies show that the catalytic effect of the metal is not some constant electrostatic effect, that can be assessed from gas phase studies, but a reflection of the dielectric effect of the specific environment...
  11. pmc On unjustifiably misrepresenting the EVB approach while simultaneously adopting it
    Shina C L Kamerlin
    Department of Chemistry, University of Southern California, 3620 McClintock Avenue, Los Angeles, California 90089, USA
    J Phys Chem B 113:10905-15. 2009
    ..which where presented as verification of the unreliability of the EVB model were in fact obtained by the use of incorrect parameters, without comparing to the correct surface obtained by our program...
  12. pmc Enzyme millisecond conformational dynamics do not catalyze the chemical step
    Andrei V Pisliakov
    Department of Chemistry SGM 418, University of Southern California, 3620 McClintock Avenue, Los Angeles, CA 90089, USA
    Proc Natl Acad Sci U S A 106:17359-64. 2009
    ..Nevertheless, the precise nature of this coupling is a question of great importance...
  13. pmc On the relationship between thermal stability and catalytic power of enzymes
    Maite Roca
    Department of Chemistry, University of Southern California, 418 SGM Building, 3620 McClintock Avenue, Los Angeles, California 90089 1062, USA
    Biochemistry 46:15076-88. 2007
    ..Thus, the optimized catalysts are less stable. This trend is clearly observed in the DHFR case...
  14. ncbi Origin of the temperature dependence of isotope effects in enzymatic reactions: the case of dihydrofolate reductase
    Hanbin Liu
    Department of Chemistry, University of Southern California, 3620 McClintock Avenue, Los Angeles, California 90089 1062, USA
    J Phys Chem B 111:7852-61. 2007
    ....
  15. pmc A new paradigm for electrostatic catalysis of radical reactions in vitamin B12 enzymes
    Pankaz K Sharma
    Department of Chemistry, University of Southern California, 418 SGM Building, 3620 McClintock Avenue, Los Angeles, CA 90089 1062, USA
    Proc Natl Acad Sci U S A 104:9661-6. 2007
    ..The trick used by B(12) enzymes may, in fact, be a very powerful new strategy in enzyme design...
  16. ncbi What are the roles of substrate-assisted catalysis and proximity effects in peptide bond formation by the ribosome?
    Pankaz K Sharma
    University of Southern California, SGM 418, 3620 McClintock Avenue, Los Angeles, California 90089 1062, USA
    Biochemistry 44:11307-14. 2005
    ..The nature of these effects and their relationship to catalytic factors in modern enzymes is analyzed and discussed...
  17. ncbi Towards accurate ab initio QM/MM calculations of free-energy profiles of enzymatic reactions
    Edina Rosta
    Department of Chemistry, University of Southern California, 3620 South McClintock Avenue, Los Angeles, California 90089 1062, USA
    J Phys Chem B 110:2934-41. 2006
    ..Our advance allows one to explore consistently various mechanistic and catalytic proposals while using ab initio (ai) QM/MM approaches...
  18. ncbi Dynamical contributions to enzyme catalysis: critical tests of a popular hypothesis
    Mats H M Olsson
    Department of Chemistry, University of Southern California, 3620 McClintock Avenue, Los Angeles, California 90089 1062, USA
    Chem Rev 106:1737-56. 2006
  19. pmc Transition state theory can be used in studies of enzyme catalysis: lessons from simulations of tunnelling and dynamical effects in lipoxygenase and other systems
    Mats H M Olsson
    Department of Chemistry, University of Southern California, 3620 South McClintock Avenue, Los Angeles, CA 90089 1062, USA
    Philos Trans R Soc Lond B Biol Sci 361:1417-32. 2006
    ....
  20. ncbi Electrostatic basis for enzyme catalysis
    Arieh Warshel
    Department of Chemistry, University of Southern California, SGM Building 418, 3620 McClintock Avenue, Los Angeles, California 90089 1062, USA
    Chem Rev 106:3210-35. 2006
  21. ncbi Using the constrained DFT approach in generating diabatic surfaces and off diagonal empirical valence bond terms for modeling reactions in condensed phases
    Gongyi Hong
    Department of Chemistry, University of Southern California, 3620 S McClintock Ave, Los Angeles, 90089 1062, USA
    J Phys Chem B 110:19570-4. 2006
    ..It is found that, at least for the test case of S(N)()2 reactions, the off diagonal element does not change significantly upon moving from the gas phase to solutions and thus the EVB assumption is valid and extremely useful...
  22. ncbi Modeling electrostatic effects in proteins
    Arieh Warshel
    University of Southern California, 418 SGM Building, 3620 McClintock Avenue, Los Angeles, CA 90089 1062, USA
    Biochim Biophys Acta 1764:1647-76. 2006
    ....
  23. ncbi Electrostatic contributions to binding of transition state analogues can be very different from the corresponding contributions to catalysis: phenolates binding to the oxyanion hole of ketosteroid isomerase
    Arieh Warshel
    Department of Chemistry, University of Southern California, 418 SGM Building, 3620 McClintock Avenue, Los Angeles, California 90089 1062, USA
    Biochemistry 46:1466-76. 2007
    ..It seems to us that this work provides an excellent example of the need for computational studies in analyzing key experimental findings about enzyme catalysis...
  24. pmc Exploring pathways and barriers for coupled ET/PT in cytochrome c oxidase: a general framework for examining energetics and mechanistic alternatives
    Mats H M Olsson
    University of Southern California, 3620 McClintock Avenue, Department of Chemistry, SGM 418, Los Angeles, CA 90089 1062, USA
    Biochim Biophys Acta 1767:244-60. 2007
    ....
  25. ncbi Electrostatic contributions to protein stability and folding energy
    Maite Roca
    Department of Chemistry, University of Southern California, 418 SGM Building, 3620 McClintock Avenue, Los Angeles, CA 90089 1062, USA
    FEBS Lett 581:2065-71. 2007
    ..Although this description should be examined by further microscopic studies, the practical use of the current approach seems to offer a powerful tool for protein design and for studies of the energetics of protein folding...
  26. ncbi The catalytic effect of dihydrofolate reductase and its mutants is determined by reorganization energies
    Hanbin Liu
    Department of Chemistry, University of Southern California, 3620 McClintock Avenue, Los Angeles, California 90089 1062, USA
    Biochemistry 46:6011-25. 2007
    ..Thus, as far as catalysis is concerned, the change in the activation barrier is due to the change in the electrostatic preorganization energy...
  27. doi Effective approach for calculations of absolute stability of proteins using focused dielectric constants
    Spyridon Vicatos
    Department of Chemistry, University of Southern California, Los Angeles, California 90089, USA
    Proteins 77:670-84. 2009
    ..8 kcal/mole compared to the observed values, making our method very promising for estimating protein stability. It also provides valuable insight into the complex electrostatic phenomena taking place in folded proteins...