Transition-state theory, dynamics, and narrow time scale separation in the rate-promoting vibrations model of enzyme catalysis

The power of transition-state theory (TST) for understanding enzymes is evidenced by its recent use in the design and synthesis of highly active de novo enzymes. However, dynamics can influence reaction kinetics, and some studies of rate-promoting vibrations even claim that dynamical theories instead of TST are needed to understand enzymatic reaction mechanisms. For the rate-promoting vibration (RPV) model of enzyme catalysis [Antoniou et al., J. Chem. Phys. 2004, 121, 6442], a reactive flux correlation function analysis shows that dynamical effects do slow the kinetics. However, the RPV model also shows extremely long-lived correlations because the RPV and the bath are not directly coupled. Additionally, earlier studies of the RPV model show a narrow time scale separation due to a small 5kT barrier. Thus earlier findings based on the RPV model may have little bearing on the properties of real enzymes. The intrinsic reaction coordinate (IRC) reveals that the RPV is an important component of the reaction coordinate at early and late stages of the pathway, but the RPV is not an important component of the reaction coordinate direction at the transition state. The unstable eigenmode from harmonic TST (which coincides with the IRC at the saddle point) gives a larger transmission coefficient than the coordinate used in the correlation functions of Antoniou et al. Thus while TST cannot predict the transmission coefficient, the RPV model suggests that TST can provide mechanistic insights on elementary steps in enzyme catalysis. Finally, we propose a method for using the transition-state ensemble as predicted from harmonic TST to distinguish promoting vibrations from other more mundane bath variables.