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Theoretical Modeling of Enzyme Reactions: The Thermodynamics of Formation of Compound 0 in Horseradish Peroxidase

2008; American Chemical Society; Volume: 112; Issue: 10 Linguagem: Inglês

10.1021/jp0774692

1520-6106

Costantino Zazza, Andrea Amadei, Amedeo Palma, Nico Sanna, Simone Tatoli, Massimiliano Aschi,

Photosynthetic Processes and Mechanisms

In this paper, by using the perturbed matrix method (PMM) in combination with basic statistical mechanical relations both based on nanosecond time-scale molecular dynamics (MD) simulations, we quantitatively address the thermodynamics of compound 0 (Cpd 0) formation in horseradish peroxidase (HRP) enzyme. Our results, in the same trend of low-temperature experimental data, obtained in cryoenzymology studies indicate that such a reaction can be described essentially as a stepwise spontaneous process: a first step mechanically constrained, strongly exothermic proton transfer from the heme−H2O2 complex to the conserved His42, followed by a solvent−protein relaxation involving a large entropy increase. Critical evaluation of PMM/MD data also reveals the crucial role played by specific residues in the reaction pocket and, more in general, by the conformational fluctuations of the overall environment in physiological conditions.