Proteins feel more than they see: fine-tuning of binding affinity by properties of the non-interacting surface.
Protein-protein complexes orchestrate most cellular processes such as transcription, signal transduction and apoptosis. The factors governing their affinity remain elusive however, especially when it comes to describing dissociation rates (koff). Here we demonstrate that, next to direct contributions from the interface, the non-interacting surface (NIS) also plays an important role in binding affinity, especially polar and charged residues. Their percentage on the NIS is conserved over orthologous complexes indicating an evolutionary selection pressure. Their effect on binding affinity can be explained by long-range electrostatic contributions and surface-solvent interactions that are known to determine the local frustration of the protein complex surface. Including these in a simple model significantly improves the affinity prediction of protein complexes from structural models. The impact of mutations outside the interacting surface on binding affinity is supported by experimental alanine scanning mutagenesis data. These results enable the development of more sophisticated and integrated biophysical models of binding affinity and open new directions in experimental control and modulation of biomolecular interactions.
Bijvoet Center for Biomolecular Research, Faculty of Science, Department of Chemistry, Utrecht University, Padualaan 8, 3584CH Utrecht, The Netherlands. Electronic address: kastriti@embl.de.
Panagiotis L
PL
Kastritis
Bijvoet Center for Biomolecular Research, Faculty of Science, Department of Chemistry, Utrecht University, Padualaan 8, 3584CH Utrecht, The Netherlands.
João P G L M
JP
Rodrigues
Bijvoet Center for Biomolecular Research, Faculty of Science, Department of Chemistry, Utrecht University, Padualaan 8, 3584CH Utrecht, The Netherlands.
Gert E
GE
Folkers
Bijvoet Center for Biomolecular Research, Faculty of Science, Department of Chemistry, Utrecht University, Padualaan 8, 3584CH Utrecht, The Netherlands.
Rolf
R
Boelens
Bijvoet Center for Biomolecular Research, Faculty of Science, Department of Chemistry, Utrecht University, Padualaan 8, 3584CH Utrecht, The Netherlands. Electronic address: a.m.j.j.bonvin@uu.nl.
Alexandre M J J
AM
Bonvin
D018360:Crystallography, X-Ray; D057927:Hydrophobic and Hydrophilic Interactions; D008958:Models, Molecular; D046912:Multiprotein Complexes / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D054730:Protein Interaction Domains and Motifs; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism*; D055672:Static Electricity; D014867:Water
D046912:Multiprotein Complexes; D011506:Proteins; D014867:Water
buried surface area; hydrophilicity; hydrophobicity; k(off); protein–protein complexes