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Hotspot coevolution at protein-protein interfaces is a key identifier of native protein complexes
- Publication Year :
- 2019
- Publisher :
- Cold Spring Harbor Laboratory, 2019.
-
Abstract
- Protein-protein interactions play a key role in mediating numerous biological functions, with more than half the proteins in living organisms existing as either homo- or hetero-oligomeric assemblies. Protein subunits that form oligomers minimize the free energy of the complex, but exhaustive computational search-based docking methods have not comprehensively addressed the protein docking challenge of distinguishing a natively bound complex from non-native forms. In this study, we propose a scoring function, KFC-E, that accounts for both conservation and coevolution of putative binding hotspot residues at protein-protein interfaces. For a benchmark set of 53 bound complexes, KFC-E identifies a near-native binding mode as the top-scoring pose in 38% and in the top 5 in 55% of the complexes. For a set of 17 unbound complexes, KFC-E identifies a near-native pose in the top 10 ranked poses in more than 50% of the cases. By contrast, a scoring function that incorporates information on coevolution at predicted non-hotspots performs poorly by comparison. Our study highlights the importance of coevolution at hotspot residues in forming natively bound complexes and suggests a novel approach for coevolutionary scoring in protein docking.Author SummaryA fundamental problem in biology is to distinguish between the native and non-native bound forms of protein-protein complexes. Experimental methods are often used to detect the native bound forms of proteins but, are demanding in terms of time and resources. Computational approaches have proven to be a useful alternative; they sample the different binding configurations for a pair of interacting proteins and then use an heuristic or physical model to score them. In this study we propose a new scoring approach, KFC-E, which focuses on the evolutionary contributions from a subset of key interface residues (hotspots) to identify native bound complexes. KFC-E capitalizes on the wealth of information in protein sequence databases by incorporating residue-level conservation and coevolution of putative binding hotspots. As hotspot residues mediate the binding energetics of protein-protein interactions, we hypothesize that the knowledge of putative hotspots coupled with their evolutionary information should be helpful in the identification of native bound protein-protein complexes.
- Subjects :
- 0303 health sciences
010304 chemical physics
Protein protein
Protein subunit
Computational biology
01 natural sciences
Identifier
03 medical and health sciences
Protein sequencing
Docking (molecular)
0103 physical sciences
Hotspot (geology)
Native protein
Macromolecular docking
Coevolution
030304 developmental biology
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....77802fcc8c81536ffdc4724f87b6ec5c
- Full Text :
- https://doi.org/10.1101/698233