The CAPRI (Critical Assessment of Predicted Interactions) and CASP (Critical Assessment of protein Structure Prediction) experiments have demonstrated the power of community-wide tests of methodology in assessing the current state of the art and spurring progress in the very challenging areas of protein docking and structure prediction. We sought to bring the power of community-wide experiments to bear on a very challenging protein design problem that provides a complementary but equally fundamental test of current understanding of protein-binding thermodynamics. We have generated a number of designed protein-protein interfaces with very favorable computed binding energies but which do not appear to be formed in experiments, suggesting that there may be important physical chemistry missing in the energy calculations. A total of 28 research groups took up the challenge of determining what is missing: we provided structures of 87 designed complexes and 120 naturally occurring complexes and asked participants to identify energetic contributions and/or structural features that distinguish between the two sets. The community found that electrostatics and solvation terms partially distinguish the designs from the natural complexes, largely due to the nonpolar character of the designed interactions. Beyond this polarity difference, the community found that the designed binding surfaces were, on average, structurally less embedded in the designed monomers, suggesting that backbone conformational rigidity at the designed surface is important for realization of the designed function. These results can be used to improve computational design strategies, but there is still much to be learned; for example, one designed complex, which does form in experiments, was classified by all metrics as a nonbinder.
Bibliographical noteFunding Information:
The authors thank Sameer Velankar and Marc Lensink for their help in coordinating this experiment and Raik Grunberg for many helpful suggestions on a draft. S.J.F. was supported by a long-term fellowship from the Human Frontier Science Program . S.J.W. is Canada Research Chair Tier 1, funded by the Canadian Institutes of Health Research . Research in the Baker laboratory was supported by the Howard Hughes Medical Institute , the Defense Advanced Research Projects Agency , the National Institutes of Health Yeast Resource Center , and the Defense Threat Reduction Agency .
Copyright 2020 Elsevier B.V., All rights reserved.
- computational protein design
- conformational plasticity
- negative design
- protein-protein interactions