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QM/MM study of l-lactate oxidation by flavocytochrome b2
N Gillet1, J J Ruiz-Pernía, A de la Lande
1Laboratoire de Chimie-Physique, CNRS UMR 8000, Université Paris Sud, Bâtiment 349 - Campus d'Orsay. 15, avenue Jean Perrin, 91405 Cedex Orsay, France. natacha.gillet@kit.edu.
Physical Chemistry Chemical Physics : PCCP
|May 26, 2016
Summary
Flavocytochrome b2 (Fcb2) catalyzes l-lactate oxidation via hydride transfer. Simulations reveal a step-wise mechanism in wild-type Fcb2, differing from concerted mechanisms in variants, influenced by enzyme structure and electrostatics.
Area of Science:
- Biochemistry
- Computational Chemistry
- Enzyme Mechanisms
Background:
- Flavocytochrome b2 (Fcb2) is a key enzyme in lactate metabolism.
- Understanding its catalytic mechanism is crucial for biochemical research.
Purpose of the Study:
- To elucidate the catalytic mechanism of l-lactate oxidation by Fcb2.
- To investigate the roles of specific residues (R289, D282N, Y254L) and environmental factors in catalysis.
Main Methods:
- Hybrid Quantum Mechanics/Molecular Mechanics (QM/MM) simulations.
- Density Functional Theory (DFT) for single-point energy corrections.
- Free energy surface calculations to model reaction pathways.
Main Results:
- Identified a step-wise hydride transfer mechanism in wild-type Fcb2 with R289 in a distal conformation.
- Observed a concerted mechanism in other modeled systems (WT with R289 proximal, D282N, Y254L variants).
- Highlighted the influence of electrostatic environment and steric factors on the catalytic process.
Conclusions:
- The catalytic mechanism of Fcb2 is sensitive to conformational changes and mutations.
- Environmental factors significantly modulate the hydride transfer process.
- The study provides detailed insights into enzyme-substrate interactions and reaction dynamics.
