ABSTRACT
I. Introduction ...................................................................................................................... 621
II. Methods for Simulations of Chemical Processes in Enzymes........................................ 623
A. QM/MM Molecular Orbital Methods ...................................................................... 624
B. EVB as a Reliable QM/MM Method ...................................................................... 625
III. Simulating Nuclear Quantum Mechanical Effects in Condensed Phase ........................ 626
A. The Dispersed Polaron (Spin Boson) Model........................................................... 626
B. Quantized Classical Path Simulations ..................................................................... 627
IV. Simulations of the KIE and Nuclear Quantum Mechanical Effects
in Enzymatic Reactions ................................................................................................... 630
A. Systematic Studies of Hydride Transfer in Solutions ............................................. 630
B. Simulating NQM Effects in LDH by a Microscopically
Based Quasiharmonic Model and a QCP Treatment .............................................. 630
C. Nuclear Quantum Mechanical Effects in Carbonic Anhydrase .............................. 631
D. Nuclear Quantum Mechanical Effects in Alcohol Dehydrogenase ........................ 632
E. Lipoxygenase and the Large Tunneling Limit ........................................................ 634
V. What is the Catalytic Contribution from Nuclear Quantum Mechanical Effects?......... 635
VI. What Can and What Cannot be Learned from Simulations of Isotope Effects?............ 636
A. The Use of Vibronic Models in Studies of Isotope Effects .................................... 636
B. Using Calculated and Observed Isotope Effects as a Tool for
Validating Single Only Simulations of NQM and Determining
the Catalytic Contributions of NQM Effects........................................................... 637
C. Determining the Concertedness of Enzymatic Reactions by the KIE.................... 638
D. Dynamical Effects and Promoting Modes............................................................... 638
VII. Concluding Remarks........................................................................................................ 639
Acknowledgments ........................................................................................................................ 640
References..................................................................................................................................... 640
Understanding enzymatic reactions and realizing what makes them so efficient is one of the
challenges of modern biochemistry. Although important elements of this puzzle were thoroughly
investigated by biochemical and structural studies, the source of the catalytic power of enzymes is
not entirely understood. General statements that suggest that the enzyme binds the transition state
better than the ground state do not really increase the knowledge about enzyme catalysis since the
real question is how this differential binding is accomplished and which catalytic groups are
responsible. To discuss this rate enhancement we will consider a generic enzymatic reaction using
the equation
Eþ SO
ES
! EP! Eþ P ð23:1Þ
Here, E, S, and P are the enzyme, substrate and product, respectively, and ES, EP, and ES
are the
enzyme-substrate complex, enzyme product complex and enzyme transition state, respectively.
