Abstract
BackgroundProtein-protein docking for proteins with large conformational changes was analyzed by using interaction fingerprints, one of the scales for measuring similarities among complex structures, utilized especially for searching near-native protein-ligand or protein-protein complex structures. Here, we have proposed a combined method for analyzing protein-protein docking by taking large conformational changes into consideration. This combined method consists of ensemble soft docking with multiple protein structures, refinement of complexes, and cluster analysis using interaction fingerprints and energy profiles.ResultsTo test for the applicability of this combined method, various CaM-ligand complexes were reconstructed from the NMR structures of unbound CaM. For the purpose of reconstruction, we used three known CaM-ligands, namely, the CaM-binding peptides of cyclic nucleotide gateway (CNG), CaM kinase kinase (CaMKK) and the plasma membrane Ca2+ ATPase pump (PMCA), and thirty-one structurally diverse CaM conformations. For each ligand, 62000 CaM-ligand complexes were generated in the docking step and the relationship between their energy profiles and structural similarities to the native complex were analyzed using interaction fingerprint and RMSD. Near-native clusters were obtained in the case of CNG and CaMKK.ConclusionsThe interaction fingerprint method discriminated near-native structures better than the RMSD method in cluster analysis. We showed that a combined method that includes the interaction fingerprint is very useful for protein-protein docking analysis of certain cases.
Highlights
Protein-protein docking for proteins with large conformational changes was analyzed by using interaction fingerprints, one of the scales for measuring similarities among complex structures, utilized especially for searching near-native protein-ligand or protein-protein complex structures
Decoy structures were obtained from the rigid-body docking simulations using one of the 3 peptides (CNG, CaM kinase kinase (CaMKK), or PMCA) as a ligand and CaM multi-structures generated from nuclear magnetic resonance (NMR) analysis (Figure 2)
We used the cluster analysis to determine the abilities of Tc-interaction fingerprints (IFPs) and root mean square distance (RMSD) in dividing the decoys into groups of similar decoys according to the Tc-IFP or RMSD threshold
Summary
Protein-protein docking for proteins with large conformational changes was analyzed by using interaction fingerprints, one of the scales for measuring similarities among complex structures, utilized especially for searching near-native protein-ligand or protein-protein complex structures. A network of protein-protein interactions is considered scale-free type, rather than random [1,2,3], suggesting that from this network of protein-protein interactions we can find proteins interacting with various targets Such proteins, referred to as hub proteins, are intrinsically disordered protein [1,4,5], which is one of the problems associated with predicting protein complexes from the rigid-body docking approach because of protein flexibility. There are different methods for generating multiple structures: molecular dynamics (MD), normal-mode analysis (NMA), and 3dimensional (3D) structural data generated by nuclear magnetic resonance (NMR). These methods are often combined to account for backbone and side-chain flexibilities [7,8,9,10].
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