Why Do Empirical Valence Bond Simulations Yield Accurate Arrhenius Plots?

Area of Science:

• Computational chemistry
• Biophysical chemistry
• Enzyme kinetics

Background:

• Computer simulations using the empirical valence bond (EVB) method accurately predict thermodynamic activation parameters for enzyme reactions.
• Understanding the factors influencing activation enthalpies and entropies in enzymatic processes is crucial for predicting reaction mechanisms and temperature dependence.

Purpose of the Study:

• To analyze why EVB simulations accurately capture activation enthalpies and entropies.
• To investigate the sensitivity of these thermodynamic parameters to the parametrization of the reactive potential energy function.
• To determine the factors controlling activation entropy in enzymatic reactions.

Main Methods:

• Utilized the empirical valence bond (EVB) method for computer simulations.
• Examined the solution reference reaction for ketosteroid isomerase (acetate-catalyzed deprotonation).
• Modified the EVB potential to shift activation and reaction free energies.
• Analyzed a concerted hydride and proton transfer reaction in hydroxybutyrate dehydrogenase.

Main Results:

• EVB simulations accurately reproduced experimentally determined activation parameters for ketosteroid isomerase.
• Activation entropy (ΔS‡) remained largely invariant despite significant shifts in free energies.
• ΔS‡ was found to be determined by the mixture of underlying force fields in the transition state region.
• This mixture's coefficients showed minimal change within reasonable EVB potential modifications, indicating robust entropy estimates.

Conclusions:

• EVB simulations provide reliable predictions of enzyme reaction thermodynamics.
• Activation entropy in enzymatic reactions is robust and primarily dependent on the transition state's force field composition.
• The EVB method offers a robust approach for calculating activation entropies, even for complex reactions.