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Abstract Comparative docking is based on experimentally determined structures of protein‐protein complexes (templates), following the paradigm that proteins with similar sequences and/or structures form similar complexes. Modeling utilizing structure similarity of target monomers to template complexes significantly expands structural coverage of the interactome. Template‐based docking by structure alignment can be performed for the entire structures or by aligning targets to the bound interfaces of the experimentally determined complexes. Systematic benchmarking of docking protocols based on full and interface structure alignment showed that both protocols perform similarly, with top 1 docking success rate 26%. However, in terms of the models' quality, the interface‐based docking performed marginally better. The interface‐based docking is preferable when one would suspect a significant conformational change in the full protein structure upon binding, for example, a rearrangement of the domains in multidomain proteins. Importantly, if the same structure is selected as the top template by both full and interface alignment, the docking success rate increases 2‐fold for both top 1 and top 10 predictions. Matching structural annotations of the target and template proteins for template detection, as a computationally less expensive alternative to structural alignment, did not improve the docking performance. Sophisticated remote sequence homology detection added templates to the pool of those identified by structure‐based alignment, suggesting that for practical docking, the combination of the structure alignment protocols and the remote sequence homology detection may be useful in order to avoid potential flaws in generation of the structural templates library. 

Abstract Structures of proteins and protein–protein complexes are determined by the same physical principles and thus share a number of similarities. At the same time, there could be differences because in order to function, proteins interact with other molecules, undergo conformations changes, and so forth, which might impose different restraints on the tertiary versus quaternary structures. This study focuses on structural properties of protein–protein interfaces in comparison with the protein core, based on the wealth of currently available structural data and new structure‐based approaches. The results showed that physicochemical characteristics, such as amino acid composition, residue–residue contact preferences, and hydrophilicity/hydrophobicity distributions, are similar in protein core and protein–protein interfaces. On the other hand, characteristics that reflect the evolutionary pressure, such as structural composition and packing, are largely different. The results provide important insight into fundamental properties of protein structure and function. At the same time, the results contribute to better understanding of the ways to dock proteins. Recent progress in predicting structures of individual proteins follows the advancement of deep learning techniques and new approaches to residue coevolution data. Protein core could potentially provide large amounts of data for application of the deep learning to docking. However, our results showed that the core motifs are significantly different from those at protein–protein interfaces, and thus may not be directly useful for docking. At the same time, such difference may help to overcome a major obstacle in application of the coevolutionary data to docking—discrimination of the intramolecular information not directly relevant to docking.