Journal
PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS
Volume 89, Issue 9, Pages 1125-1133Publisher
WILEY
DOI: 10.1002/prot.26085
Keywords
binding residue; coarse‐ grained dynamics; geometric hashing; metal‐ binding; site prediction
Categories
Funding
- Department of Biotechnology
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This study introduces a method to improve metal-binding site prediction using the Geometric Hashing algorithm. By screening metal-specific amino acids in the structure ensemble, the residues for Ca2+, Zn2+, Mg2+, Cu2+, and Fe3+ binding sites can be predicted with superior performance compared to existing methods.
Metal ions are central to the molecular function of many proteins. Thus their knowledge in experimentally determined structure is important; however, such structures often lose bound metal ions during sample preparation. Identification of these metal-binding site(s) becomes difficult when the receptor is novel and/or their conformations differ in the bound/unbound states. Locating such sites in theoretical models also poses a challenge due to the uncertainties with side-chain modeling. We address the problem by employing the Geometric Hashing algorithm to create a template library of functionally important binding sites and match query structures with the available templates. The matching is done on the structure ensemble obtained from coarse-grained molecular dynamics simulation, where metal-specific amino acids are screened to infer the true site. Test on 1347 non-redundant monomer protein structures show that Ca2+, Zn2+, Mg2+, Cu2+, and Fe3+ binding site residues can be classified at 0.92, 0.95, 0.80, 0.90, and 0.92 aggregate performance (out of 1) across all possible thresholds. The performance for Ca2+ and Zn2+ is notably superior in comparison to state-of-the-art methods like IonCom and MIB. Specific case studies show that additionally predicted metal-binding site residues in proteins have features necessary for ion binding. These include new sites not predicted by other methods. The use of coarse-grained dynamics thus provides a generalized approach to improve metal-binding site prediction. The work is expected to contribute to improving our ability to correctly predict protein molecular function where knowledge of metal binding is a key requirement.
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