title: Predicting Ca2+ -binding sites using refined carbon clusters.
abstract: Identifying Ca(2+) -binding sites in proteins is the first step toward understanding the molecular basis of diseases related to Ca(2+) -binding proteins. Currently, these sites are identified in structures either through X-ray crystallography or NMR analysis. However, Ca(2+) -binding sites are not always visible in X-ray structures due to flexibility in the binding region or low occupancy in a Ca(2+) -binding site. Similarly, both Ca(2+) and its ligand oxygens are not directly observed in NMR structures. To improve our ability to predict Ca(2+) -binding sites in both X-ray and NMR structures, we report a new graph theory algorithm (MUG(C) ) to predict Ca(2+) -binding sites. Using carbon atoms covalently bonded to the chelating oxygen atoms, and without explicit reference to side-chain oxygen ligand co-ordinates, MUG(C) is able to achieve 94% sensitivity with 76% selectivity on a dataset of X-ray structures composed of 43 Ca(2+) -binding proteins. Additionally, prediction of Ca(2+) -binding sites in NMR structures was obtained by MUG(C) using a different set of parameters, which were determined by the analysis of both Ca(2+) -constrained and unconstrained Ca(2+) -loaded structures derived from NMR data. MUG(C) identified 20 of 21 Ca(2+) -binding sites in NMR structures inferred without the use of Ca(2+) constraints. MUG(C) predictions are also highly selective for Ca(2+) -binding sites as analyses of binding sites for Mg(2+) , Zn(2+) , and Pb(2+) were not identified as Ca(2+) -binding sites. These results indicate that the geometric arrangement of the second-shell carbon cluster is sufficient not only for accurate identification of Ca(2+) -binding sites in NMR and X-ray structures but also for selective differentiation between Ca(2+) and other relevant divalent cations.
authors: Department of Mathematics and Statistics, Georgia State University, Atlanta, GA 30303, USA.
authors: Kun
authors: K
authors: Zhao
authors: Xue
authors: X
authors: Wang
authors: Hing C
authors: HC
authors: Wong
authors: Robert
authors: R
authors: Wohlhueter
authors: Michael P
authors: MP
authors: Kirberger
authors: Guantao
authors: G
authors: Chen
authors: Jenny J
authors: JJ
authors: Yang
mesh_terms: D000465:Algorithms; D000818:Animals; D001665:Binding Sites; D002118:Calcium / Q000737:chemistry* / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000737:chemistry* / Q000378:metabolism*; D002147:Calmodulin / Q000737:chemistry / Q000378:metabolism; D002244:Carbon / Q000737:chemistry*; D002417:Cattle; D018797:Cell Cycle Proteins / Q000737:chemistry / Q000378:metabolism; D019295:Computational Biology; D018360:Crystallography, X-Ray; D030562:Databases, Protein; D006801:Humans; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D019906:Nuclear Magnetic Resonance, Biomolecular; D011485:Protein Binding
chemical_list: C472752:CETN2 protein, human; D002135:Calcium-Binding Proteins; D002147:Calmodulin; D018797:Cell Cycle Proteins; D002244:Carbon; D002118:Calcium