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Motions of Allosteric and Orthosteric Ligand-Binding Sites in Proteins are Highly Correlated

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    Motions of Allosteric and Orthosteric Ligand-Binding Sites in Proteins are Highly Correlated
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    † ‡ § †Center for Quantitative Biology, ‡BNLMS, State Key Laboratory for Structural Chemistry of Unstable and Stable Species, College of Chemistry and Molecular Engineering, and §Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China
    *E-mail: [email protected] (L.L.); Fax: (+86)10-62751725.
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    Journal of Chemical Information and Modeling

    Cite this: J. Chem. Inf. Model. 2016, 56, 9, 1725–1733
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    https://doi.org/10.1021/acs.jcim.6b00039
    Published August 31, 2016
    Copyright © 2016 American Chemical Society
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    Abstract

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    Allostery is the phenomenon in which a ligand binding at one site affects other sites in the same macromolecule. Allostery has important roles in many biological processes. Theoretically, all nonfibrous proteins are potentially allosteric. However, few allosteric proteins have been validated, and the identification of novel allosteric sites remains a challenge. The motion of residues and subunits underlies protein function; therefore, we hypothesized that the motions of allosteric and orthosteric sites are correlated. We utilized a data set of 24 known allosteric sites from 23 monomer proteins to calculate the correlations between potential ligand-binding sites and corresponding orthosteric sites using a Gaussian network model (GNM). Most of the known allosteric site motions showed high correlations with corresponding orthosteric site motions, whereas other surface cavities did not. These high correlations were robust when using different structural data for the same protein, such as structures for the apo state and the orthosteric effector-binding state, whereas the contributions of different frequency modes to motion correlations depend on the given protein. The high correlations between allosteric and orthosteric site motions were also observed in oligomeric allosteric proteins. We applied motion correlation analysis to predict potential allosteric sites in the 23 monomer proteins, and some of these predictions were in good agreement with published experimental data. We also performed motion correlation analysis to identify a novel allosteric site in 15-lipoxygenase (an enzyme in the arachidonic acid metabolic network) using recently reported activating compounds. Our analysis correctly identified this novel allosteric site along with two other sites that are currently under experimental investigation. Our study demonstrates that the motions of allosteric sites are highly correlated with the motions of orthosteric sites. Our correlation analysis method provides new tools for predicting potential allosteric sites.

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    • Figure S1. Cases of relatively high-frequency modes playing much more important roles in motion correlations between known allosteric sites and their corresponding orthosteric sites. Table S1. Ranking of Z-Scorecavity_mall values and volumes for all cavities except for known allosteric and orthosteric sites in the test proteins. Table S2. Rank of allosteric site volume in all cavities except the orthosteric site of test proteins, rank of number of highly correlated residues (top 30%) with orthosteric residues, and total rank of the three most-correlated residues TCi_OSall (TCi_OSall = ∑j∈orthosteric siteTCijall) in each cavity. Table S3. spearman correlation coefficient between Z-Scorecavity_mall value ranking and simple volume ranking. Table S4. Z-Score and volume ranking of test proteins using the Apo state structure. Table S5. Z-Score and volume ranking of test proteins using only structures with bound orthosteric effectors. Table S6. Cα root mean square differences between different states of test proteins. Table S7. Details of cavities predicted as potential allosteric sites. Table S8. Flexibility P-value of known allosteric sites predicted by PARS (PDF)

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    Cite this: J. Chem. Inf. Model. 2016, 56, 9, 1725–1733
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    https://doi.org/10.1021/acs.jcim.6b00039
    Published August 31, 2016
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