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The influence of interdomain interactions on the intradomain motions in yeast phosphoglycerate kinase: a molecular dynamics study.

ABSTRACT: A 3-ns molecular dynamics simulation in explicit solvent was performed to examine the inter- and intradomain motions of the two-domain enzyme yeast phosphoglycerate kinase without the presence of substrates. To elucidate contributions from individual domains, simulations were carried out on the complete enzyme as well as on each isolated domain. The enzyme is known to undergo a hinge-bending type of motion as it cycles from an open to a closed conformation to allow the phosphoryl transfer occur. Analysis of the correlation of atomic movements during the simulations confirms hinge bending in the nanosecond timescale: the two domains of the complete enzyme exhibit rigid body motions anticorrelated with respect to each other. The correlation of the intradomain motions of both domains converges, yielding a distinct correlation map in the enzyme. In the isolated domain simulations-in which interdomain interactions cannot occur-the correlation of domain motions no longer converges and shows a very small correlation during the same simulation time. This result points to the importance of interdomain contacts in the overall dynamics of the protein. The secondary structure elements responsible for interdomain contacts are also discussed.

SUBMITTER: Balog E

PROVIDER: S-EPMC1796818 | biostudies-literature | 2007 Mar

REPOSITORIES: biostudies-literature

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The influence of interdomain interactions on the intradomain motions in yeast phosphoglycerate kinase: a molecular dynamics study.

Balog Erika E Laberge Monique M Fidy Judit J

Biophysical journal 20061208 5

A 3-ns molecular dynamics simulation in explicit solvent was performed to examine the inter- and intradomain motions of the two-domain enzyme yeast phosphoglycerate kinase without the presence of substrates. To elucidate contributions from individual domains, simulations were carried out on the complete enzyme as well as on each isolated domain. The enzyme is known to undergo a hinge-bending type of motion as it cycles from an open to a closed conformation to allow the phosphoryl transfer occur. ...[more]

PMID: 17158564

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Project description:Phosphoglycerate kinase (PGK) catalyzes an important ATP-generating step in glycolysis. PGK1 deficiency is an uncommon X-linked inherited disorder, generally characterized by various combinations of non-spherocytic hemolytic anemia, neurological dysfunctions, and myopathies. Patients rarely exhibit all three clinical features. To provide a molecular framework to the different pathological manifestations, all known mutations were reviewed and 16 mutant enzymes, obtained as recombinant forms, were functionally and structurally characterized. Most mutations heavily affect thermal stability and to a different extent catalytic efficiency, in line with the remarkably low PGK activity clinically observed in the patients. Mutations grossly impairing protein stability, but moderately affecting kinetic properties (p.I47N, p.L89P, p.C316R, p.S320N, and p.A354P) present the most homogeneous correlation with the clinical phenotype. Patients carrying these mutations display hemolytic anemia and neurological disorders, and,except for p.A354P variant, no myopaty. Variants highly perturbed in both catalytic efficiency (p.G158V, p.D164V, p.K191del, D285V, p.D315N, and p.T378P) and heat stability (all, but p.T378P) result to be mainly associated with myopathy alone. Finally, mutations faintly affecting molecular properties (p.R206P, p.E252A, p.I253T, p.V266M, and p.D268N) correlate with a wide spectrum of clinical symptoms. These are the first studies that correlate the clinical symptoms with the molecular properties of the mutant enzymes. All findings indicate that the different clinical manifestations associated with PGK1 deficiency chiefly depend on the distinctive type of perturbations caused by mutations in the PGK1 gene, highlighting the need for determination of the molecular properties of PGK variants to assist in prognosis and genetic counseling. However, the clinical symptoms can not be understood only on the bases of molecular properties of the mutant enzyme. Different (environmental, metabolic, genetic and/or epigenetic) intervening factors can contribute toward the expression of PGK deficient clinical phenotypes.

Dataset Information

The influence of interdomain interactions on the intradomain motions in yeast phosphoglycerate kinase: a molecular dynamics study.

Publications

The influence of interdomain interactions on the intradomain motions in yeast phosphoglycerate kinase: a molecular dynamics study.

Similar Datasets

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