Abstract:
:We examine the relationship between binding affinity and interface size for reversible protein-protein interactions (PPIs), using cytokines from the tumor necrosis factor (TNF) superfamily and their receptors as a test case. Using surface plasmon resonance, we measured single-site binding affinities for binding of the large receptor TNFR1 to its ligands TNFα (K(D) = 1.4 ± 0.4 nM) and lymphotoxin-α (K(D) = 50 ± 10 nM), and also for binding of the small receptor Fn14 to TWEAK (K(D) = 70 ± 10 nM). We additionally assembled data for all other TNF-TNFR family complexes for which reliable single-site binding affinities have been reported. We used these values to calculate the binding efficiencies, defined as binding energy per square angstrom of surface area buried at the contact interface, for nine of these complexes for which cocrystal structures are available, and compared the results to those for a set of 144 protein-protein complexes with published affinities. The results show that the most efficient PPI complexes generate ~20 cal mol(-1) Å(-2) of binding energy. A minimal contact area of ~500 Å(2) is required for a stable complex, required to generate sufficient interaction energy to pay the entropic cost of colocalizing two proteins from 1 M solution. The most compact and efficient TNF-TNFR complex was the BAFF-BR3 complex, which achieved ~80% of the maximal achievable binding efficiency. Other small receptors also gave high binding efficiencies, while the larger receptors generated only 44-49% of this limit despite interacting primarily through just a single small domain. The results provide new insight into how much binding energy can be generated by a PPI interface of a given size, and establish a quantitative method for predicting how large a natural or engineered contact interface must be to achieve a given level of binding affinity.
journal_name
Biochemistryjournal_title
Biochemistryauthors
Day ES,Cote SM,Whitty Adoi
10.1021/bi301039tsubject
Has Abstractpub_date
2012-11-13 00:00:00pages
9124-36issue
45eissn
0006-2960issn
1520-4995journal_volume
51pub_type
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