The Activation Entropy Change in Enzymatic Reaction Catalyzed by Isochorismate-Pyruvate Lyase of Pseudomonas Aeruginosa PchB

TL;DR

This study uses advanced QM/MM MD simulations to accurately calculate the activation entropy in an enzymatic reaction, clarifying the entropic contributions and resolving debates about whether the reaction is entropy-driven.

Contribution

First application of QM/MM MD simulations to compute activation entropy from temperature-dependent free energy profiles in enzyme catalysis.

Findings

Calculated entropy change agrees with experimental data

Conformational ordering contributes to entropy penalty

Method provides quantitative insights into enthalpy-entropy balance

Abstract

The elucidation of entropic contribution to enzyme catalysis has been debated over decades. The recent experimentally measured activation enthalpy and entropy, for chorismate rearrangement reaction in PchB brings up a hotly debated issue whether the chorismate mutase catalyzed reaction is entropy-driven reaction. Extensive configurational sampling combined with quantum mechanics/molecular mechanics molecular dynamics (QM/MM MD) provides an approach to calculate entropic contribution in condensed phase reactions. Complete reaction pathway is exploited by QM/MM MD simulations at DFT and SCC-DFTB levels. The overall entropy change calculated at SCC-DFTB level QM/MM MD simulations, is close agreement with the experimental value. Conformation analysis indicates that the self-ordering of chorismate in the active site of PchB also contributes to total entropy change. This entropy penalty including conformational transformation entropy and activation entropy cannot be intuitively speculated from the crystal structure that only acts as a stationary state along the reaction pathway of PchB catalyzed reaction. This is the first time to use QM/MM MD simulations to calculate the activation entropy from the temperature dependence of reliable free energy profiles with extensive simulation time. The reasonable insight in enthalpy/entropy scheme clarifies the detailed entropy change and provides a quantitative tool to the contradicted experimental results.