Free Energy Profile of Domain Movement in Ligand-Free Citrate Synthase

Roccatano, Danilo and Steven, Hayward (2019) Free Energy Profile of Domain Movement in Ligand-Free Citrate Synthase. The Journal of Physical Chemistry B, 123 (9). pp. 1998-2004. ISSN 1520-6106

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Free Energy Profile of Domain Movement in Ligand-Free Citrate Synthase
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Citrate synthase plays a fundamental role in the metabolic cycle of the cell. Its catalytic mechanism is complex involving the binding of two substrates that cause a domain movement. In this paper, we used classical molecular dynamics simulations and umbrella sampling simulations to determine the potential of mean force along a reaction coordinate for the domain movement in ligand-free citrate synthase from pig (Sus Scrofa). The results show that at 293 K, the closed-domain conformation has a ~4 kbT higher energy than the open-domain conformation. In a simple two-state model, this difference means that the enzyme spends 98% of the time in the open-domain conformation ready to receive the substrate, oxaloacetate, rather than the closed-domain conformation where the binding site would be inaccessible to the substrate. Given that experimental evidence indicates that the binding of oxaloacetate induces at least partial closure, this would imply an induced-fit mechanism which we argue is applicable to all enzymes with a functional domain movement for reasons of catalytic efficiency. A barrier of 4 kbT gives an estimation of the mean first passage time in the range 1-10 microseconds.

Keywords:Molecular dynamics simulations, Protein domain motion, First passage time, Free energy barrier
Subjects:C Biological Sciences > C770 Biophysical Science
F Physical Sciences > F320 Chemical Physics
F Physical Sciences > F165 Biomolecular Chemistry
Divisions:College of Science > School of Mathematics and Physics
ID Code:34997
Deposited On:10 Apr 2019 08:06

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