Protein–protein interactions: General trends in the relationship between binding affinity and interfacial buried surface area

Abstract

Protein-protein interactions play key roles in many cellular processes and their affinities and specificities are finely tuned to the functions they perform. Here, we present a study on the relationship between binding affinity and the size and chemical nature of protein-protein interfaces. Our analysis focuses on heterodimers and includes curated structural and thermodynamic data for 113 complexes. We observe a direct correlation between binding affinity and the amount of surface area buried at the interface. For a given amount of surface area buried, the binding affinity spans four orders of magnitude in terms of the dissociation constant (K d ). Across the entire dataset, we observe no obvious relationship between binding affinity and the chemical composition of the interface. We also calculate the free energy per unit surface area buried, or ''surface energy density,'' of each heterodimer. For interfacial surface areas between 500 and 2000 Å 2 , the surface energy density decreases as the buried surface area increases. As the buried surface area increases beyond about 2000 Å 2 , the surface energy density levels off to a constant value. We believe that these analyses and data will be useful for researchers with an interest in understanding, designing or inhibiting protein-protein interfaces.

“Velcro” Engineering of High Affinity CD47 Ectodomain as Signal Regulatory Protein α (SIRPα) Antagonists That Enhance Antibody-dependent Cellular Phagocytosis

“…Recent work by Chen et al (32) has shown a positive correlation between binding affinity and the buried surface area at proteinprotein interfaces. We therefore explored the possibility of "artificially" increasing the buried surface area between CD47 and SIRP␣ as a means of increasing affinity.…”

Determinants of Substrate Specificity in APOBEC3B

“…93 Interfaces were filtered to only show those with more than 500 A^2 of surface area. 94 Structures which have a greater number of monomers in their asymmetric unit can show the same interface multiple times, and this is counteracted by only labeling each interface once. …”

Trans-membrane Signaling in Photosynthetic State Transitions

“…In the cyt b 6 f structure from C. reinhardtii (PDB code 1Q90), residues 51-68 are buried within the hydrophobic domain of the membrane, implying a structure impediment to interaction with the Stt7 N-terminal domain, which is outside of the membrane in the p side aqueous phase. Moreover, the polyglycine hinge of the Rieske iron-sulfur protein subunit, proposed as a possible site of interaction between Stt7 and the cyt b 6 f complex, has a surface area of 340 Å 2 (PDB code 4OGQ), which is small compared with the most frequent range of interfacial surface areas for interprotein interactions of 500 -1000 Å 2 (42). Alternatively, significant in vitro kinase activity is demonstrated in this study with purified Stt7 kinase under reducing conditions, which implies a role for the p side cysteine residues Cys 68 -Cys 73 .…”