Complementarity of structure ensembles in protein-protein binding

Raik Grünberg*, Johan Leckner* & Michael Nilges. Institut Pasteur.
 

Our understanding of protein-protein interaction is caught in a contradiction: on the one hand,experimental rates of association suggest that, in many cases, practically every collision between two partner proteins leads to the formation of the complex. On the other hand, we often fail to predict the correct orientation of a protein complex because the two free partners simply don't sufficiently fit. This discrepancy is commonly explained by a fuzzy notion of induced fit, or by the assumption that the bound conformations is present in the structure ensembles of the two unbound proteins. However, both models appear to be inconsistent with our current knowledge about the forces and time scales of recognition.

In this study, we try to incorporate the additional dimensions of receptor and ligand variability into our picture of the protein-protein binding process. We performed two sets of molecular dynamics simulations for the unbound (free) structures of 17 receptor and 16 ligand proteins and applied shape-driven rigid body docking to all combinations of representative receptor and ligand snapshots as well as the free structure. In total, we analysed and compared 2,106,368 solutions from 4114 exhaustive rigid body dockings between 693 conformations of 33 different proteins. The cross-docking of ensemble snapshots increases the chances to find near native orientations. Our results suggest that there are complementary conformations within the free receptor and ligand ensembles, which, however are in general not necessarily related to the bound structure. In addition, we also performed molecular dynamics simulations on all 17 complexes and analysed the flexibility of free and bound proteins. Our results indicate that binding may not necessarily occur at the cost of entropy. We propose a refined model of the protein-protein recognition process that is combining the ideas of conformer selection and induced fit and is in better aggreement with our current understanding of interaction forces, time scales and kinetic data.

* these authors contributed equally to the work