Community-wide assessment of protein-interface modeling suggests improvements to design methodology

Sarel J. Fleishman, Timothy A. Whitehead, Eva Maria Strauch, Jacob E. Corn, Sanbo Qin, Huan Xiang Zhou, Julie C. Mitchell, Omar N.A. Demerdash, Mayuko Takeda-Shitaka, Genki Terashi, Iain H. Moal, Xiaofan Li, Paul A. Bates, Martin Zacharias, Hahnbeom Park, Jun Su Ko, Hasup Lee, Chaok Seok, Thomas Bourquard, Julie BernauerAnne Poupon, Jérôme Azé, Seren Soner, Şefik Kerem Ovali, Pemra Ozbek, Nir Ben Tal, Türkan Haliloglu, Howook Hwang, Thom Vreven, Brian G. Pierce, Zhiping Weng, Laura Pérez-Cano, Carles Pons, Juan Fernández-Recio, Fan Jiang, Feng Yang, Xinqi Gong, Libin Cao, Xianjin Xu, Bin Liu, Panwen Wang, Chunhua Li, Cunxin Wang, Charles H. Robert, Mainak Guharoy, Shiyong Liu, Yangyu Huang, Lin Li, Dachuan Guo, Ying Chen, Yi Xiao, Nir London, Zohar Itzhaki, Ora Schueler-Furman, Yuval Inbar, Vladimir Potapov, Mati Cohen, Gideon Schreiber, Yuko Tsuchiya, Eiji Kanamori, Daron M. Standley, Haruki Nakamura, Kengo Kinoshita, Camden M. Driggers, Robert G. Hall, Jessica L. Morgan, Victor L. Hsu, Jian Zhan, Yuedong Yang, Yaoqi Zhou, Panagiotis L. Kastritis, Alexandre M.J.J. Bonvin, Weiyi Zhang, Carlos J. Camacho, Krishna P. Kilambi, Aroop Sircar, Jeffrey J. Gray, Masahito Ohue, Nobuyuki Uchikoga, Yuri Matsuzaki, Takashi Ishida, Yutaka Akiyama, Raed Khashan, Stephen Bush, Denis Fouches, Alexander Tropsha, Juan Esquivel-Rodríguez, Daisuke Kihara, P. Benjamin Stranges, Ron Jacak, Brian Kuhlman, Sheng You Huang, Xiaoqin Zou, Shoshana J. Wodak, Joel Janin, David Baker

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)289-302
Number of pages14
JournalJournal of molecular biology
Volume414
Issue number2
DOIs
StatePublished - Nov 25 2011

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Keywords

  • computational protein design
  • conformational plasticity
  • negative design
  • protein-protein interactions

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

Cite this

Fleishman, S. J., Whitehead, T. A., Strauch, E. M., Corn, J. E., Qin, S., Zhou, H. X., Mitchell, J. C., Demerdash, O. N. A., Takeda-Shitaka, M., Terashi, G., Moal, I. H., Li, X., Bates, P. A., Zacharias, M., Park, H., Ko, J. S., Lee, H., Seok, C., Bourquard, T., ... Baker, D. (2011). Community-wide assessment of protein-interface modeling suggests improvements to design methodology. Journal of molecular biology, 414(2), 289-302. https://doi.org/10.1016/j.jmb.2011.09.031