Cold Spots in Protein Binding

Understanding the energetics and architecture of protein-binding interfaces is important for basic research and could potentially facilitate the design of novel binding domains for biotechnological applications. It is well accepted that a few key residues at binding interfaces (binding hot spots) ar...

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Bibliographic Details
Published in:Trends in biochemical sciences (Amsterdam. Regular ed.) 2016-09, Vol.41 (9), p.739-745
Main Authors: Shirian, Jason, Sharabi, Oz, Shifman, Julia M.
Format: Article
Language:English
Subjects:
binding affinity
binding energetics
binding landscapes
Humans
Protein Binding
Protein Engineering
Protein Interaction Mapping
Proteins - chemistry
Proteins - genetics
Proteins - metabolism
protein–protein interactions
saturation mutagenesis
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Summary:Understanding the energetics and architecture of protein-binding interfaces is important for basic research and could potentially facilitate the design of novel binding domains for biotechnological applications. It is well accepted that a few key residues at binding interfaces (binding hot spots) are responsible for contributing most to the free energy of binding. In this opinion article, we introduce a new concept of ‘binding cold spots’, or interface positions occupied by suboptimal amino acids. Such positions exhibit a potential for affinity enhancement through various mutations. We give several examples of cold spots from different protein-engineering studies and argue that identification of such positions is crucial for studies of protein evolution and protein design. Every protein–protein interaction (PPI) contains cold-spot positions, or positions where several mutations could lead to affinity and hence fitness improvement. We see two scenarios for cold-spot occurrence. In the first scenario, there is no intermolecular interaction at a cold spot; in the second scenario, the existing interaction is highly unfavorable. Cold-spot positions can be identified experimentally through saturation mutagenesis or through phage and yeast surface display-based methods. Cold-spot positions can be predicted through an in silico saturation mutagenesis method. Cold-spot positions are present in both high- and low-affinity PPIs and are preferable sites for enhancing binding affinity and specificity.
ISSN:0968-0004
1362-4326
DOI:10.1016/j.tibs.2016.07.002