Low-resolution structural modeling of protein interactome

Abstract

Structural characterization of protein–protein interactions across the broad spectrum of scales is key to our understanding of life at the molecular level. Low-resolution approach to protein interactions is needed for modeling large interaction networks, given the significant level of uncertainties in large biomolecular systems and the high-throughput nature of the task. Since only a fraction of protein structures in interactome are determined experimentally, protein docking approaches are increasingly focusing on modeled proteins. Current rapid advancement of template-based modeling of protein–protein complexes is following a long standing trend in structure prediction of individual proteins. Protein–protein templates are already available for almost all interactions of structurally characterized proteins, and about one third of such templates are likely correct.

Modelling three-dimensional protein structures for applications in drug design

“…Increasing reliability of fully automated modelling pipelines allows models to be generated on a proteomic scale, as for the structural characterisation of the entire human kinome [91]. Another enthralling area is the prediction of protein–protein complexes on an omics scale [5,92,93]. It remains to be seen whether or not this enterprise will become conducive to drug discovery and when, for example in the design of protein–protein interaction inhibitors.…”

“…Visualisation of valid models is not merely a decorative offshoot of modelling, rather a focal point where disparate facets of research efforts can amalgamate and converge into a detailed view of the underlying mechanistic basis, which in turn can become the driving force for further advances. It should be kept in mind that, even at relatively low resolution, ‘any level of physical characterisation of a protein, as opposed to its absence, is valuable’ [5]. …”

Structural Perspectives on the Evolutionary Expansion of Unique Protein-Protein Binding Sites

“…The structural characterization of complexes should thus become one of the most important challenges and future targets in the field of structural genomics (39). Many computational methods (1,17,21,25) are being used in an attempt to fill the gap in experimental coverage of protein complexes, and these methods rely on comparative modeling of structures, threading, or docking (26). It is unclear, however, to what extent protein interactions are conserved and whether protein complexes from remotely related species can be used to infer interactions in humans.…”

“…Numerous computational methods have been designed to close the gap in the experimental structural coverage of proteomes and interactomes, particularly for human (1,17,21,25). These methods rely on two major strategies: comparative modeling/threading of protein complexes and docking (26). Questions arise, however, regarding the suitability of many structural complexes for modeling the human interactome (27,28) and the use of structural templates from other organisms for modeling human protein interfaces.…”

Template-based prediction of protein function

“…Here we focus exclusively on so-called “template”-based approaches, in which the function of a protein is assigned based primarily on its similarity to other proteins whose function is known. The wide applicability of such approaches is highlighted by the observation that, in general, there will be at least one, and usually several, proteins in structural databases that carries out a similar function using a mechanism similar to a query protein of interest [9,10,11,12]. This suggests that there are many new directions where protein structural information can be applied and, most significantly, used on a genome-wide scale [13*].…”