Predicting Ca2+‐binding sites using refined carbon clusters |
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Authors: | Kun Zhao Xue Wang Hing C. Wong Robert Wohlhueter Michael P. Kirberger Guantao Chen Jenny J. Yang |
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Affiliation: | 1. Department of Mathematics and Statistics, Georgia State University, Atlanta, Georgia 30303;2. Department of Chemistry, Georgia State University, Atlanta, Georgia 30303 |
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Abstract: | Identifying Ca2+‐binding sites in proteins is the first step toward understanding the molecular basis of diseases related to Ca2+‐binding proteins. Currently, these sites are identified in structures either through X‐ray crystallography or NMR analysis. However, Ca2+‐binding sites are not always visible in X‐ray structures due to flexibility in the binding region or low occupancy in a Ca2+‐binding site. Similarly, both Ca2+ and its ligand oxygens are not directly observed in NMR structures. To improve our ability to predict Ca2+‐binding sites in both X‐ray and NMR structures, we report a new graph theory algorithm (MUGC) to predict Ca2+‐binding sites. Using carbon atoms covalently bonded to the chelating oxygen atoms, and without explicit reference to side‐chain oxygen ligand co‐ordinates, MUGC is able to achieve 94% sensitivity with 76% selectivity on a dataset of X‐ray structures composed of 43 Ca2+‐binding proteins. Additionally, prediction of Ca2+‐binding sites in NMR structures was obtained by MUGC using a different set of parameters, which were determined by the analysis of both Ca2+‐constrained and unconstrained Ca2+‐loaded structures derived from NMR data. MUGC identified 20 of 21 Ca2+‐binding sites in NMR structures inferred without the use of Ca2+ constraints. MUGC predictions are also highly selective for Ca2+‐binding sites as analyses of binding sites for Mg2+, Zn2+, and Pb2+ were not identified as Ca2+‐binding sites. These results indicate that the geometric arrangement of the second‐shell carbon cluster is sufficient not only for accurate identification of Ca2+‐binding sites in NMR and X‐ray structures but also for selective differentiation between Ca2+ and other relevant divalent cations. © Proteins 2012. © 2012 Wiley Periodicals, Inc. |
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Keywords: | Ca2+‐binding proteins graph theory carbon clusters side‐chain center of mass NMR |
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