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ABSTRACT: Cellular functions are performed through protein-protein interactions; therefore, identification of these interactions is crucial for understanding biological processes. Recent studies suggest that knowledge-based approaches are more useful than 'blind' docking for modeling at large scales. However, a caveat of knowledge-based approaches is that they treat molecules as rigid structures. The Protein Data Bank (PDB) offers a wealth of conformations. Here, we exploited ensemble of the conformations in predictions by a knowledge-based method, PRISM. We tested 'difficult' cases in a docking-benchmark dataset, where the unbound and bound protein forms are structurally different. Considering alternative conformations for each protein, the percentage of successfully predicted interactions increased from ~26% to 66%, and 57% of the interactions were successfully predicted in an 'unbiased' scenario, in which data related to the bound forms were not utilized. If the appropriate conformation, or relevant template interface, is unavailable in the PDB, PRISM could not predict the interaction successfully. The pace of the growth of the PDB promises a rapid increase of ensemble conformations emphasizing the merit of such knowledge-based ensemble strategies for higher success rates in protein-protein interaction predictions on an interactome-scale. We constructed the structural network of ERK interacting proteins as a case study.
Journal of Proteome Research 04/2013; · 5.11 Impact Factor
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ABSTRACT: The growing perception that diseases are often consequences of multiple molecular abnormalities rather than being the result of a single defect highlights the importance of network-centric view in therapeutic approaches. Protein interaction networks may contribute to understanding of disease, assist in drug design and discovery. Here, we review some recent advances in disease-associated protein interaction networks taking a structural approach. We first describe structural aspects of protein-protein interactions and properties of protein interfaces as related to drug design; we address protein interactions in a network perspective; in particular, we illustrate how integrating protein interfaces onto interaction networks can guide the identification of selective drug targets or drugs targeting multiple proteins in a network.
Current pharmaceutical design 05/2012; · 4.41 Impact Factor
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ABSTRACT: Proteins function through their interactions, and the availability of protein interaction networks could help in understanding cellular processes. However, the known structural data are limited and the classical network node-and-edge representation, where proteins are nodes and interactions are edges, shows only which proteins interact; not how they interact. Structural networks provide this information. Protein-protein interface structures can also indicate which binding partners can interact simultaneously and which are competitive, and can help forecasting potentially harmful drug side effects. Here, we use a powerful protein-protein interactions prediction tool which is able to carry out accurate predictions on the proteome scale to construct the structural network of the extracellular signal-regulated kinases (ERK) in the mitogen-activated protein kinase (MAPK) signaling pathway. This knowledge-based method, PRISM, is motif-based, and is combined with flexible refinement and energy scoring. PRISM predicts protein interactions based on structural and evolutionary similarity to known protein interfaces.
Current Opinion in Structural Biology 05/2012; 22(3):367-77. · 9.42 Impact Factor
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ABSTRACT: Conformational selection emerges as a theme in macromolecular interactions. Data validate it as a prevailing mechanism in protein-protein, protein-DNA, protein-RNA, and protein-small molecule drug recognition. This raises the question of whether this fundamental biomolecular binding mechanism can be used to improve drug docking and discovery. Actually, in practice this has already been taking place for some years in increasing numbers. Essentially, it argues for using not a single conformer, but an ensemble. The paradigm of conformational selection holds that because the ensemble is heterogeneous, within it there will be states whose conformation matches that of the ligand. Even if the population of this state is low, since it is favorable for binding the ligand, it will bind to it with a subsequent population shift toward this conformer. Here we suggest expanding it by first modeling all protein interactions in the cell by using Prism, an efficient motif-based protein-protein interaction modeling strategy, followed by ensemble generation. Such a strategy could be particularly useful for signaling proteins, which are major targets in drug discovery and bind multiple partners through a shared binding site, each with some-minor or major-conformational change.
Methods in molecular biology (Clifton, N.J.) 01/2012; 819:59-74.
