Simulating Enzyme Catalysis and Protein Action

The landmark paper of Warshel and Levitt (J. Mol. Bio. 103 p227, 1976) paved the way for quantitative studies of enzymatic reactions. This work introduced the hybrid Quantum mechanical/Molecular mechanics (QM/MM) method and a microscopic dielectric model that have represented entire enzyme-substrate complex in solution. This facilitated the first consistent modeling of the catalytic effect of an enzyme. Our group continued to lead the field by further developing QM/MM methods, including the powerful Empirical Valence Bond (EVB) approach, simulating the dynamics of enzymatic reactions and introducing the use of free energy perturbation methods to such reactions. These studies clarified the relationship between reactions in solution and enzymes and established the catalytic role of preorganized active sites. The book on Computer Modeling of Chemical Reactions in Enzymes and Solutions is at present the only book that gives a detailed description of the field. Our current studies continue in pusing the frontiers of the field focusing on (i) developing rigorous yet effective ways for evaluation of activation free energies of enzymatic reactions. This includes the use of ab initio potential surfaces with the corresponding EVB surfaces as reference states in free energy perturbation studies, (ii) modeling classes of enzymes of major biological importance, (iii) modeling quantum mechanical tunneling processes in proteins, (iv) studies of entropic effects in catalysis and binding. Our projects include:

  • DNA and RNA Cleaving Enzymes
    • DNA-Polymerase
    • Staphylococcus Nuclease
  • Other Systems
    • Ribonuclease
    • Acetylcholine esterase
    • Aldose reductase
    • Carbonic Anhydrase
    • Hydride Transfer: Lactate Dehydrogenase (LDH), Alcohol Dehydrogenase (ADH)
    • Dehalogenase (DhlA)
  • Method Development
    • Developing new quantum mechanical simulation methods (with correct description of the relavant energetics)