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Structural energetics of protein-carbohydrate interactions: Insights derived from the study of lysozyme binding to its natural saccharide inhibitors.

ABSTRACT: High-sensitivity isothermal titration calorimetry was used to characterize the binding of the glycohydrolitic enzyme hen egg-white lysozyme to its natural saccharide inhibitors, chitobiose and chitrotriose. Measurements were done at a pH of 4.7, in the 15 degrees C -45 degrees C temperature range. Using a structural-energetic parameterization derived previously for lectin-carbohydrate associations, both binding enthalpies and entropies for the present systems and for the complex of chitobiose with turkey egg-white lysozyme from the literature were correctly accounted for. These observations suggest that both lysozymes and lectins follow the same structural-energetic behavior in the binding to their ligands. From the analysis of lysozyme data in conjunction with other binding data reported in the literature, an ad hoc parameterization of DeltaCp for protein-carbohydrate complexes was derived for the first time. The novel parameters for both polar and apolar surface areas differed significantly from correlations obtained previously from model compounds and protein-folding data. As DeltaCp is extremely sensitive to changes in solvent structure, this finding indicates that protein-carbohydrate complexes have distinctive hydration properties. According to our analysis, the dehydration of polar groups is the major cause for the observed decrease in DeltaCp, which implies that these groups behave hydrophobically. The contribution of apolar surface areas was found of the expected sign, but their specific weight is much smaller than those obtained in other correlations. This small contribution to DeltaCp is consistent with Lemieux's hypothesis of a low degree of hydration of apolar surfaces on carbohydrates.

SUBMITTER: Garcia-Hernandez E

PROVIDER: S-EPMC2312411 | biostudies-literature | 2003 Jan

REPOSITORIES: biostudies-literature

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Structural energetics of protein-carbohydrate interactions: Insights derived from the study of lysozyme binding to its natural saccharide inhibitors.

García-Hernández Enrique E Zubillaga Rafael A RA Chavelas-Adame Eneas A EA Vázquez-Contreras Edgar E Rojo-Domínguez Arturo A Costas Miguel M

Protein science : a publication of the Protein Society 20030101 1

High-sensitivity isothermal titration calorimetry was used to characterize the binding of the glycohydrolitic enzyme hen egg-white lysozyme to its natural saccharide inhibitors, chitobiose and chitrotriose. Measurements were done at a pH of 4.7, in the 15 degrees C -45 degrees C temperature range. Using a structural-energetic parameterization derived previously for lectin-carbohydrate associations, both binding enthalpies and entropies for the present systems and for the complex of chitobiose wi ...[more]

PMID: 12493836

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Project description:BackgroundTuberculosis has become a major health problem being the second leading cause of death worldwide. Mycobacterium tuberculosis secretes a virulence factor, protein tyrosine phosphatase B (mPTPB) in the cytoplasm of host macrophage which suppresses its natural innate immune response and helps the pathogen survive and proliferate in the phagosome. The present study aims at indentifying potent inhibitors of mPTPB by using computational approaches of ligand based molecular modeling and docking studies.ResultsA 3D QSAR model was developed using a set of benzofuran salicylic acid based mPTPB inhibitors with experimentally known IC50 values. The model was generated using the statistical method of principle component regression analysis in combination with step wise forward variable selection algorithm. It was observed that steric and hydrophobic descriptors positively contribute towards the inhibitory activity of the ligands. The developed model had a robust internal as well as external predictive power as indicated by the q(2) value of 0.8920 and predicted r(2) value of 0.8006 respectively. Hence, the generated model was used to screen a large set of naturally occurring chemical compounds and predict their biological activity to identify more potent natural compounds targeting mPTPB. The two top potential hits (with pIC50 value of 1.459 and 1.677 respectively) had a similar interaction pattern as that of the most potent compound (pIC50 = 1.42) of the congeneric series.ConclusionThe contour plot provided a better understanding of the relationship between structural features of substituted benzofuran salicylic acid derivatives and their activities which would facilitate design of novel mPTPB inhibitors. The QSAR modeling was used to obtain an equation, correlating the important steric and hydrophobic descriptors with the pIC50 value. Thus, we report two natural compounds of inhibitory nature active against mPTPB enzyme of Mycobacterium tuberculosis. These inhibitors have the potential to evolve as lead molecules in the development of drugs for the treatment of tuberculosis.

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Structural energetics of protein-carbohydrate interactions: Insights derived from the study of lysozyme binding to its natural saccharide inhibitors.

Publications

Structural energetics of protein-carbohydrate interactions: Insights derived from the study of lysozyme binding to its natural saccharide inhibitors.

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