SIMULATION OF PROTON AND HYDRIDE TRANSFER IN ENZYMES

Summary

Principal Investigator: Sharon Hammes-Schiffer
Abstract: The broad, long-term objectives of this research are to elucidate the fundamental principles and mechanisms of hydrogen transfer in enzyme catalysis and to address unresolved issues in biologically important systems. These objectives will be accomplished with computational methods that include electronic and nuclear quantum effects, as well as the motion of the entire solvated enzyme. The calculations will probe the roles of electrostatics, hydrogen bonding, hydrogen tunneling, and protein motion in enzyme reactions. The four enzyme reactions that will be studied have been chosen on the basis of their biomedical importance and the availability of relevant experimental data. The first specific aim centers on the enzyme dihydrofolate reductase (DHFR), which is required for normal folate metabolism in prokaryotes and eukaryotes. This enzyme maintains tetrahydrofolate levels required to support the biosynthesis of purines, pyrimidines, and amino acids. DHFR is medically relevant in that inhibition of DHFR with potent antifolates has been used successfully in cancer chemotherapy. The second specific aim centers on the enzyme dihydroorotate dehydrogenase (DHOD). This enzyme catalyzes the only redox reaction in the biosynthesis of pyrimidines, which are required for the supply of precursors for RNA and DMA synthesis. DHOD is medically relevant in that the immunosuppressive effects of inhibiting this enzyme have been used therapeutically to treat diseases such as rheumatoid arthritis. The third specific aim centers on the enzyme lipoxygenase. This enzyme aids in the production of leukotrienes and lipoxins, which regulate responses in inflammation and immunity. In mammals, lipoxygenases are medically relevant in that inhibitors have been used as drug agents to treat diseases such as asthma, atherosclerosis, psoriasis, and cancer. The fourth specific aim centers on the enzyme ketosteroid isomerase (KSI), which catalyzes the isomerization of steroids. In mammals, this enzyme is medically relevant in that it controls the synthesis of steroid hormones. Deficiencies of KSI and related enzymes in humans lead to a wide range of diseases and health problems. All of these studies are relevant to public health because the elucidation of the mechanisms will facilitate the development of more effective drugs for a broad range of diseases, including cancer, asthma, malaria, and rheumatoid arthritis.
Funding Period: ----------------1998 - ---------------2011-
more information: NIH RePORT

Top Publications

  1. pmc Impact of mutation on proton transfer reactions in ketosteroid isomerase: insights from molecular dynamics simulations
    Dhruva K Chakravorty
    Department of Chemistry, 104 Chemistry Building, Pennsylvania State University, University Park, Pennsylvania 16802, USA
    J Am Chem Soc 132:7549-55. 2010
  2. pmc Temporally overlapped but uncoupled motions in dihydrofolate reductase catalysis
    C Tony Liu
    Department of Chemistry, Pennsylvania State University, University Park, PA 16802, USA
    Biochemistry 52:5332-4. 2013
  3. pmc Functional significance of evolving protein sequence in dihydrofolate reductase from bacteria to humans
    C Tony Liu
    Department of Chemistry, Pennsylvania State University, University Park, PA 16802, USA
    Proc Natl Acad Sci U S A 110:10159-64. 2013
  4. pmc Hydrogen bonding in the active site of ketosteroid isomerase: electronic inductive effects and hydrogen bond coupling
    Philip Hanoian
    Department of Chemistry, Pennsylvania State University, University Park, PA 16802, USA
    Biochemistry 49:10339-48. 2010
  5. pmc Coupled motions in enzyme catalysis
    Vishal C Nashine
    Department of Chemistry, The Pennsylvania State University, 414 Wartik Laboratory, University Park, PA 16802, USA
    Curr Opin Chem Biol 14:644-51. 2010
  6. pmc Long-distance communication in the HDV ribozyme: insights from molecular dynamics and experiments
    Narayanan Veeraraghavan
    Huck Institutes of Life Sciences, Pennsylvania State University, University Park, PA 16802, USA
    J Mol Biol 402:278-91. 2010
  7. pmc Proton-coupled electron transfer in solution, proteins, and electrochemistry
    Sharon Hammes-Schiffer
    Department of Chemistry, 104 Chemistry Building, Pennsylvania State University, University Park, Pennsylvania 16802, USA
    J Phys Chem B 112:14108-23. 2008
  8. pmc Impact of distal mutation on hydrogen transfer interface and substrate conformation in soybean lipoxygenase
    Sarah J Edwards
    Department of Chemistry, 104 Chemistry Building, Pennsylvania State University, University Park, Pennsylvania 16802, USA
    J Phys Chem B 114:6653-60. 2010
  9. pmc Implementation of umbrella integration within the framework of the empirical valence bond approach
    Dhruva K Chakravorty
    Department of Chemistry, 104 Chemistry Building, Pennsylvania State University, University Park, PA 16802 E mail
    J Chem Theory Comput 4:1974-1980. 2008
  10. pmc Theory of proton-coupled electron transfer in energy conversion processes
    Sharon Hammes-Schiffer
    Department of Chemistry, 104 Chemistry Building, Pennsylvania State University, University Park, Pennsylvania 16802, USA
    Acc Chem Res 42:1881-9. 2009

Scientific Experts

  • Sharon Hammes-Schiffer
  • Philip Hanoian
  • Dhruva K Chakravorty
  • Alexander V Soudackov
  • C Tony Liu
  • Narayanan Veeraraghavan
  • Sarah J Edwards
  • Stephen J Benkovic
  • Malika Kumarasiri
  • Philip C Bevilacqua
  • Vishal C Nashine
  • Michelle K Ludlow
  • Lin Wang
  • Thomas H Pringle
  • Jarrod B French
  • Nina M Goodey
  • Abir Ganguly
  • Barbara L Golden
  • Daniel Herschlag
  • Paul A Sigala
  • Gregory A Baker

Detail Information

Publications19

  1. pmc Impact of mutation on proton transfer reactions in ketosteroid isomerase: insights from molecular dynamics simulations
    Dhruva K Chakravorty
    Department of Chemistry, 104 Chemistry Building, Pennsylvania State University, University Park, Pennsylvania 16802, USA
    J Am Chem Soc 132:7549-55. 2010
    ..Moreover, small conformational changes due to stochastic thermal motions are required within this preorganized active site to facilitate the proton transfer reactions...
  2. pmc Temporally overlapped but uncoupled motions in dihydrofolate reductase catalysis
    C Tony Liu
    Department of Chemistry, Pennsylvania State University, University Park, PA 16802, USA
    Biochemistry 52:5332-4. 2013
    ....
  3. pmc Functional significance of evolving protein sequence in dihydrofolate reductase from bacteria to humans
    C Tony Liu
    Department of Chemistry, Pennsylvania State University, University Park, PA 16802, USA
    Proc Natl Acad Sci U S A 110:10159-64. 2013
    ..The data presented here provide a glimpse into the evolutionary trajectory of functional DHFR through its protein sequence space that lead to the diverged binding and catalytic properties of the E. coli and human enzymes...
  4. pmc Hydrogen bonding in the active site of ketosteroid isomerase: electronic inductive effects and hydrogen bond coupling
    Philip Hanoian
    Department of Chemistry, Pennsylvania State University, University Park, PA 16802, USA
    Biochemistry 49:10339-48. 2010
    ..These studies also provide experimentally testable predictions about the impact of mutating the distal tyrosine residues in this hydrogen bonding network on the NMR chemical shifts and electronic absorption spectra...
  5. pmc Coupled motions in enzyme catalysis
    Vishal C Nashine
    Department of Chemistry, The Pennsylvania State University, 414 Wartik Laboratory, University Park, PA 16802, USA
    Curr Opin Chem Biol 14:644-51. 2010
    ..The impact of tunneling, the possible role of vibrational coupling and the value of conformational chemical landscapes are also scrutinized...
  6. pmc Long-distance communication in the HDV ribozyme: insights from molecular dynamics and experiments
    Narayanan Veeraraghavan
    Huck Institutes of Life Sciences, Pennsylvania State University, University Park, PA 16802, USA
    J Mol Biol 402:278-91. 2010
    ..Overall, these studies indicate that small functional RNAs have the potential to communicate interactions over long distances and that wild-type RNAs may have evolved ways to prevent such interactions from interfering with catalysis...
  7. pmc Proton-coupled electron transfer in solution, proteins, and electrochemistry
    Sharon Hammes-Schiffer
    Department of Chemistry, 104 Chemistry Building, Pennsylvania State University, University Park, Pennsylvania 16802, USA
    J Phys Chem B 112:14108-23. 2008
    ..Expressions for heterogeneous rate constants and current densities for electrochemical PCET have also been derived and applied to model systems...
  8. pmc Impact of distal mutation on hydrogen transfer interface and substrate conformation in soybean lipoxygenase
    Sarah J Edwards
    Department of Chemistry, 104 Chemistry Building, Pennsylvania State University, University Park, Pennsylvania 16802, USA
    J Phys Chem B 114:6653-60. 2010
    ..This study provides insight into how the effects of distal mutations may be transmitted in enzymes to ultimately impact the catalytic rates...
  9. pmc Implementation of umbrella integration within the framework of the empirical valence bond approach
    Dhruva K Chakravorty
    Department of Chemistry, 104 Chemistry Building, Pennsylvania State University, University Park, PA 16802 E mail
    J Chem Theory Comput 4:1974-1980. 2008
    ..A modified version of the weighted histogram analysis method that shares these advantages is also proposed and implemented...
  10. pmc Theory of proton-coupled electron transfer in energy conversion processes
    Sharon Hammes-Schiffer
    Department of Chemistry, 104 Chemistry Building, Pennsylvania State University, University Park, Pennsylvania 16802, USA
    Acc Chem Res 42:1881-9. 2009
    ..Understanding the impact of these changes on the PCET rate may assist experimental efforts to enhance energy conversion processes...
  11. pmc Hybrid quantum/classical molecular dynamics simulations of the proton transfer reactions catalyzed by ketosteroid isomerase: analysis of hydrogen bonding, conformational motions, and electrostatics
    Dhruva K Chakravorty
    Department of Chemistry, 104 Chemistry Building, The Pennsylvania State University, University Park, Pennsylvania 16802, USA
    Biochemistry 48:10608-19. 2009
    ..Moreover, the conformational and electrostatic changes associated with these reactions are not limited to the active site but rather extend throughout the entire enzyme...
  12. pmc Theoretical analysis of the unusual temperature dependence of the kinetic isotope effect in quinol oxidation
    Michelle K Ludlow
    Department of Chemistry, 104 Chemistry Building, Pennsylvania State University, University Park, Pennsylvania 16802, USA
    J Am Chem Soc 131:7094-102. 2009
    ..The temperature dependence of the KIE is found to be very sensitive to the interplay among the driving force, the reorganization energy, and the vibronic coupling in this regime...
  13. pmc Mechanistic strategies in the HDV ribozyme: chelated and diffuse metal ion interactions and active site protonation
    Narayanan Veeraraghavan
    Huck Institutes of Life Sciences, The Pennsylvania State University, University Park, Pennsylvania 16802, United States
    J Phys Chem B 115:8346-57. 2011
    ..These results are consistent with a wealth of experimental data...
  14. pmc Water in the active site of ketosteroid isomerase
    Philip Hanoian
    Department of Chemistry, 104 Chemistry Building, Pennsylvania State University, University Park, Pennsylvania 16802, USA
    Biochemistry 50:6689-700. 2011
    ....
  15. pmc Computational approach for ranking mutant enzymes according to catalytic reaction rates
    Malika Kumarasiri
    Department of Chemistry, Pennsylvania State University, University Park, Pennsylvania 16802, USA
    J Phys Chem B 113:3579-83. 2009
    ..82. This general approach for ranking protein designs has implications for protein engineering and drug design...
  16. pmc Analysis of kinetic isotope effects for proton-coupled electron transfer reactions
    Sarah J Edwards
    Department of Chemistry, 104 Chemistry Building, Pennsylvania State University, University Park, Pennsylvania 16802, USA
    J Phys Chem A 113:2117-26. 2009
    ..These calculations and analyses lead to experimentally testable predictions of trends in the KIEs for PCET systems...