Quantum Effects and Protein Motion in Enzymatic Catalysis

Open Access
Agarwal, Pratul K.
Graduate Program:
Doctor of Philosophy
Document Type:
Date of Defense:
March 12, 2002
Committee Members:
  • Kenneth M Merz Jr, Committee Member
  • Sharon Hammes Schiffer, Committee Chair
  • Stephen James Benkovic, Committee Member
  • Milton Walter Cole, Committee Member
  • ring puckering
  • protein
  • enzyme
  • quantum effects
  • coupled motion
  • network of motions
  • network
  • vibrations
  • reaction coordinate
This thesis presents theoretical studies to investigate the role of quantum effects and protein motion in enzymatic catalysis. Hydrogen tunneling has been known to play a role in the enzymes which catalyze hydride transfer. Details about the nature of hydrogen tunneling and other quantum effects for these enzymes are difficult to obtain from biochemical experiments. We have used theoretical methods to investigate the enzyme liver alcohol dehydrogenase (LADH) as a prototypical system. Our results indicate that the hydride transfer in LADH is adiabatic and hydrogen tunneling does not play a critical role along the minimum energy path. In contrast, nonadiabatic effects and hydrogen tunneling are shown to be important along the more relevant straight-line reaction paths. We have also found that the donor-acceptor distance and cofactor NAD+ nicotinamide ring puckering are dominant contributors to the reaction coordinate for hydride transfer. Protein motion has been suggested as a factor influencing the activity of an enzyme. We have investigated the enzyme dihydrofolate reductase (DHFR) for a link between protein motion and hydride transfer catalyzed by this enzyme. A network of coupled promoting motions has been identified and characterized for DHFR. The present identification is based on novel hybrid quantum-classical molecular dynamics simulations. The motions in this network span timescales of femtosecond to millisecond and are found on the exterior of the protein as well as in the active site. This type of network has broad implications for an expanded role of the protein fold in catalysis and the action of ligand binding distal to the active site.