Abstract
BackgroundStructure-based computational methods are needed to help identify and characterize protein-protein complexes and their function. For individual proteins, the most successful technique is homology modelling. We investigate a simple extension of this technique to protein-protein complexes. We consider a large set of complexes of known structures, involving pairs of single-domain proteins. The complexes are compared with each other to establish their sequence and structural similarities and the relation between the two. Compared to earlier studies, a simpler dataset, a simpler structural alignment procedure, and an additional energy criterion are used. Next, we compare the Xray structures to models obtained by threading the native sequence onto other, homologous complexes. An elementary requirement for a successful energy function is to rank the native structure above any threaded structure. We use the DFIREβ energy function, whose quality and complexity are typical of the models used today. Finally, we compare near-native models to distinctly non-native models.ResultsIf weakly stable complexes are excluded (defined by a binding energy cutoff), as well as a few unusual complexes, a simple homology principle holds: complexes that share more than 35% sequence identity share similar structures and interaction modes; this principle was less clearcut in earlier studies. The energy function was then tested for its ability to identify experimental structures among sets of decoys, produced by a simple threading procedure. On average, the experimental structure is ranked above 92% of the alternate structures. Thus, discrimination of the native structure is good but not perfect. The discrimination of near-native structures is fair. Typically, a single, alternate, non-native binding mode exists that has a native-like energy. Some of the associated failures may correspond to genuine, alternate binding modes and/or native complexes that are artefacts of the crystal environment. In other cases, additional model filtering with more sophisticated tools is needed.ConclusionThe results suggest that the simple modelling procedure applied here could help identify and characterize protein-protein complexes. The next step is to apply it on a genomic scale.
Highlights
Structure-based computational methods are needed to help identify and characterize protein-protein complexes and their function
Homology modeling of a protein-protein complex requires that a structural similarity principle should hold: similar proteins should interact in a similar way
We examine the performance of a simple homology modelling approach, which could be used for large-scale studies
Summary
Structure-based computational methods are needed to help identify and characterize protein-protein complexes and their function. We compare the Xray structures to models obtained by threading the native sequence onto other, homologous complexes. Structure-based computational methods provide additional information, and are especially useful to characterize direct, physical interactions between proteins [11,12,13,14,15,16,17,18,19]. A more attractive possibility is to perform homology modelling, and exploit the ever-growing structural databases [23] to model putative protein-protein complexes [16,18]. Homology modeling of a protein-protein complex requires that a structural similarity principle should hold: similar proteins should interact in a similar way. A recent, systematic study by Aloy & Russell [24] found only a moderate correlation between sequence and structural similarity for proteinprotein complexes
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