Community-Wide Assessment of Protein-Interface Modeling Suggests Improvements to Design Methodology.
2 Institute of Molecular Biophysics [Tallahassee]
3 University of Wisconsin–Whitewater
4 Kitasato University
5 Biomolecular Modelling laboratory [London]
6 TUM - Technische Universität Munchen = Technical University Munich = Université Technique de Munich
7 SNU - Seoul National University [Seoul]
8 ORPAILLEUR - Knowledge representation, reasonning
9 AMIB - Algorithms and Models for Integrative Biology
10 PRC - Physiologie de la reproduction et des comportements [Nouzilly]
11 ChE - Department of Chemical Engineering [Bogazici]
12 TAU - Tel Aviv University
13 UMASS - University of Massachusetts Medical School [Worcester]
14 BSC-CNS - Barcelona Supercomputing Center - Centro Nacional de Supercomputacion
15 CAS - Chinese Academy of Sciences [Beijing]
16 BJUT - Beijing University of Technology
17 LBT (UPR_9080) - Laboratoire de biochimie théorique [Paris]
18 HUST - Huazhong University of Science and Technology [Wuhan]
19 Hadassah Hebrew University Medical Center [Jerusalem]
20 Weizmann Institute of Science [Rehovot, Israël]
21 Institute for Protein Research [Osaka]
22 Japan Biological Informatics Consortium [Tokyo]
23 IFREC - WPI Immunology Frontier Research Center
24 Graduate School of Information Sciences [Tohoku University]
25 OSU - Oregon State University
26 IUPUI - Indiana University - Purdue University Indianapolis
27 Bijvoet Center for Biomolecular Research [Utrecht]
28 PITT - University of Pittsburgh
29 JHU - Johns Hopkins University [Baltimore]
30 TITECH - Tokyo Institute of Technology [Tokyo]
31 UNC-Chapel Hill - Université de Caroline du Nord à Chapel Hill = University of North Carolina [Chapel Hill]
32 Purdue University [West Lafayette]
33 Dalton Cardiovascular Research Center [Columbia]
34 SickKids - The Hospital for sick children [Toronto]
35 IBBMC - Institut de biochimie et biophysique moléculaire et cellulaire
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Résumé
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.