Investigation of the mechanism of domain closure in citrate synthase by molecular dynamics simulation

Roccatano, D., Mark, A. E. and Hayward, S. (2001) Investigation of the mechanism of domain closure in citrate synthase by molecular dynamics simulation. Journal of Molecular Biology, 310 5: 1039-1053. doi:10.1006/jmbi.2001.4808


Author Roccatano, D.
Mark, A. E.
Hayward, S.
Title Investigation of the mechanism of domain closure in citrate synthase by molecular dynamics simulation
Journal name Journal of Molecular Biology   Check publisher's open access policy
ISSN 0022-2836
Publication date 2001-01-01
Sub-type Article (original research)
DOI 10.1006/jmbi.2001.4808
Volume 310
Issue 5
Start page 1039
End page 1053
Total pages 15
Place of publication London
Publisher Academic Press Ltd
Language eng
Abstract Six, 2 ns molecular dynamics simulations have been performed on the homodimeric enzyme citrate synthase. In three, both monomers were started from the open, unliganded X-ray conformation. In the remaining three, both monomers started from a closed, liganded X-ray conformation, with the ligands removed. Projecting the motion from the simulations onto the experimental domain motion revealed that the free-energy profile is rather flat around the open conformation, with steep sides. The most closed conformations correspond to hinge-bending angles of 12-14 degrees compared to the 20 degrees that occurs upon the binding of oxaloacetate. It is also found that the open, unliganded X-ray conformation is situated at the edge of the steep rise in free energy, although conformations that are about 5 degrees more open were sampled. A rigid-body essential dynamics analysis of the combined open trajectories has shown that domain motions in the direction of the closed X-ray conformation are compatible with the natural domain motion of the unliganded protein, which has just two main degrees of freedom. The simulations starting from the closed conformation suggest a free-energy profile with a small barrier in going from the closed to open conformation. A combined essential dynamics and hinge-bending analysis of a trajectory that spontaneously converts from the closed to open state shows an almost exact correspondence to the experimental transition that occurs upon ligand binding. The simulations support the conclusion from an earlier analysis of the experimental transition that the beta -hairpin acts as a mechanical hinge by attaching the small domain to the large domain through a conserved main-chain hydrogen bond and salt-bridges, and allowing rotation to occur via its two flexible termini. The results point to a mechanism of domain closure in citrate synthase that has analogy to the process of closing a door. (C) 2001 Academic Press.
Keyword Biochemistry & Molecular Biology
hinge bending
hinge axis
dynamic domains
essential dynamics analysis
rigid-body analysis
Normal-mode Analysis
Collective Motions
Protein Dynamics
Coenzyme-a
Oxaloacetate
Lysozyme
Solvent
Complex
Paths
Water
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Unknown

Document type: Journal Article
Sub-type: Article (original research)
Collection: School of Chemistry and Molecular Biosciences
 
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Created: Thu, 20 Sep 2007, 01:53:30 EST