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Electrostatic optimization of the conformational energy landscape in a metamorphic protein.

ABSTRACT: The equilibrium unfolding reaction of Ltn, a metamorphic C-class chemokine, was monitored by tryptophan fluorescence to determine unfolding free energies. Measurements revealed that addition of 150 mM NaCl stabilized the Ltn chemokine fold by approximately 1 kcal/mol. Specific mutations involving Arg23 and Arg43 also increased the stability by 1 kcal/mol, suggesting their involvement in chloride ion coordination. This interaction was confirmed by nuclear magnetic resonance (NMR) salt titration studies that revealed chemical shift perturbations localized to these residues and backbone amides within the proximal 40s loop. The effects of NaCl on the free energy landscape were further verified by ZZ-exchange NMR spectroscopy. Our results suggest that changes in the electrostatic environment modulate the Gibbs free energy of folding and alter the forward and reverse rates of interconversion. These results demonstrate how solution ions can promote metamorphic folding by adjusting the relative stabilities of two unrelated Ltn native-state structures.

SUBMITTER: Tyler RC

PROVIDER: S-EPMC3567213 | biostudies-literature | 2012 Nov

REPOSITORIES: biostudies-literature

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Electrostatic optimization of the conformational energy landscape in a metamorphic protein.

Tyler Robert C RC Wieting Jamie C JC Peterson Francis C FC Volkman Brian F BF

Biochemistry 20121102 45

The equilibrium unfolding reaction of Ltn, a metamorphic C-class chemokine, was monitored by tryptophan fluorescence to determine unfolding free energies. Measurements revealed that addition of 150 mM NaCl stabilized the Ltn chemokine fold by approximately 1 kcal/mol. Specific mutations involving Arg23 and Arg43 also increased the stability by 1 kcal/mol, suggesting their involvement in chloride ion coordination. This interaction was confirmed by nuclear magnetic resonance (NMR) salt titration s ...[more]

PMID: 23102260

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Project description:Calculations of electrostatic properties of protein-protein complexes are usually done within framework of a model with a certain set of parameters. In this paper we present a comprehensive statistical analysis of the sensitivity of the electrostatic component of binding free energy (DeltaDeltaGel) with respect with different force fields (Charmm, Amber, and OPLS), different values of the internal dielectric constant, and different presentations of molecular surface (different values of the probe radius). The study was done using the largest so far set of entries comprising 260 hetero and 2148 homo protein-protein complexes extracted from a previously developed database of protein complexes (ProtCom). To test the sensitivity of the energy calculations with respect to the structural details, all structures were energy minimized with corresponding force field, and the energies were recalculated. The results indicate that the absolute value of the electrostatic component of the binding free energy (DeltaDeltaGel) is very sensitive to the force field parameters, the minimization procedure, the values of the internal dielectric constant, and the probe radius. Nevertheless our results indicate that certain trends in DeltaDeltaGel behavior are much less sensitive to the calculation parameters. For instance, the fraction of the homo-complexes, for which the electrostatics was found to oppose binding, is 80% regardless of the force fields and parameters used. For the hetero-complexes, however, the percentage of the cases for which electrostatics opposed binding varied from 43% to 85%, depending on the protocol and parameters employed. A significant correlation was found between the effects caused by raising the internal dielectric constant and decreasing the probe radius. Correlations were also found among the results obtained with different force fields. However, despite of the correlations found, the absolute DeltaDeltaGel calculated with different force field parameters could differ more than tens of kcal/mol in some cases. Set of rules of obtaining confident predictions of absolute DeltaDeltaGel and DeltaDeltaGel sign are provided in the conclusion section.PACS codes: 87.15.A-, 87.15. km.

Dataset Information

Electrostatic optimization of the conformational energy landscape in a metamorphic protein.

Publications

Electrostatic optimization of the conformational energy landscape in a metamorphic protein.

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