Community-Wide Assessment of Protein-Interface Modeling Suggests Improvements to Design Methodology.

Sarel J Fleishman 1 Timothy A Whitehead 1 Eva-Maria Strauch 1 Jacob E Corn 1 Sanbo Qin 2 Huan-Xiang Zhou 2 Julie C Mitchell 3 Omar N A Demerdash 3 Mayuko Takeda-Shitaka 4 Genki Terashi 4 Iain H Moal 5 Xiaofan Li 5 Paul A Bates 5 Martin Zacharias 6 Hahnbeom Park 7 Jun-Su Ko 7 Hasup Lee 7 Chaok Seok 7 Thomas Bourquard 8 Julie Bernauer 9 Anne Poupon 10 Jérôme Azé 9 Seren Soner 11 Sefik Kerem Ovalı 11 Pemra Ozbek 11 Nir Ben Tal 12 Türkan Haliloglu 11 Howook Hwang 13 Thom Vreven 13 Brian G Pierce 13 Zhiping Weng 13 Laura Pérez-Cano 14 Carles Pons 14 Juan Fernández-Recio 14 Fan Jiang 15 Feng Yang 16 Xinqi Gong 16 Libin Cao 16 Xianjin Xu 16 Bin Liu 16 Panwen Wang 16 Chunhua Li 16 Cunxin Wang 16 Charles H Robert 17 Mainak Guharoy 17 Shiyong Liu 18 Yangyu Huang 18 Lin Li 18 Dachuan Guo 18 Ying Chen 18 Yi Xiao 18 Nir London 19 Zohar Itzhaki 19 Ora Schueler-Furman 19 Yuval Inbar 20 Vladimir Patapov 20 Mati Cohen 20 Gideon Schreiber 20 Yuko Tsuchiya 21 Eiji Kanamori 22 Daron M Standley 23 Haruki Nakamura 21 Kengo Kinoshita 24 Camden M Driggers 25 Robert G Hall 25 Jessica L Morgan 25 Victor L Hsu 25 Jian Zhan 26 Yuedong Yang 26 Yaoqi Zhou 26 Panagiotis L Kastritis 27 Alexandre M J J Bonvin 27 Weiyi Zhang 28 Carlos J Camacho 28 Krishna P Kilambi 29 Aroop Sircar 29 Jeffrey J Gray 29 Masahito Ohue 30 Nobuyuki Uchikoga 30 Yuri Matsuzaki 30 Takashi Ishida 30 Yutaka Akiyama 30 Raed Khashan 31 Stephen Bush 31 Denis Fouches 31 Alexander Tropsha 31 Juan Esquivel-Rodríguez 32 Daisuke Kihara 32 P Benjamin Stranges 31 Ron Jacak 31 Brian Kuhlman 31 Sheng-You Huang 33 Xiaoqin Zou 33 Shoshana J Wodak 34 Joel Janin 35 David Baker 1
8 ORPAILLEUR - Knowledge representation, reasonning
INRIA Lorraine, LORIA - Laboratoire Lorrain de Recherche en Informatique et ses Applications
9 AMIB - Algorithms and Models for Integrative Biology
LIX - Laboratoire d'informatique de l'École polytechnique [Palaiseau], LRI - Laboratoire de Recherche en Informatique, UP11 - Université Paris-Sud - Paris 11, Inria Saclay - Ile de France
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.
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Submitted on : Thursday, November 3, 2011 - 10:20:27 AM
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Sarel J Fleishman, Timothy A Whitehead, Eva-Maria Strauch, Jacob E Corn, Sanbo Qin, et al.. Community-Wide Assessment of Protein-Interface Modeling Suggests Improvements to Design Methodology.. Journal of Molecular Biology, Elsevier, 2011, in press. ⟨10.1016/j.jmb.2011.09.031⟩. ⟨inria-00637848⟩



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