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 Bernauer & 76 others Anne 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

  • 88 Citations

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
Externally publishedYes

Profile

Proteins
Physical Chemistry
Static Electricity
Thermodynamics
Protein Binding

Keywords

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

ASJC Scopus subject areas

  • Molecular Biology

Cite this

Fleishman, S. J., Whitehead, T. A., Strauch, E. M., Corn, J. E., Qin, S., Zhou, H. X., ... Baker, D. (2011). Community-wide assessment of protein-interface modeling suggests improvements to design methodology. Journal of Molecular Biology, 414(2), 289-302. DOI: 10.1016/j.jmb.2011.09.031

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

In: Journal of Molecular Biology, Vol. 414, No. 2, 25.11.2011, p. 289-302.

Research output: Contribution to journalArticle

Fleishman, SJ, Whitehead, TA, Strauch, EM, Corn, JE, Qin, S, Zhou, HX, Mitchell, JC, Demerdash, ONA, Takeda-Shitaka, M, Terashi, G, Moal, IH, Li, X, Bates, PA, Zacharias, M, Park, H, Ko, JS, Lee, H, Seok, C, Bourquard, T, Bernauer, J, Poupon, A, Azé, J, Soner, S, Ovali, ŞK, Ozbek, P, Tal, NB, Haliloglu, T, Hwang, H, Vreven, T, Pierce, BG, Weng, Z, Pérez-Cano, L, Pons, C, Fernández-Recio, J, Jiang, F, Yang, F, Gong, X, Cao, L, Xu, X, Liu, B, Wang, P, Li, C, Wang, C, Robert, CH, Guharoy, M, Liu, S, Huang, Y, Li, L, Guo, D, Chen, Y, Xiao, Y, London, N, Itzhaki, Z, Schueler-Furman, O, Inbar, Y, Potapov, V, Cohen, M, Schreiber, G, Tsuchiya, Y, Kanamori, E, Standley, DM, Nakamura, H, Kinoshita, K, Driggers, CM, Hall, RG, Morgan, JL, Hsu, VL, Zhan, J, Yang, Y, Zhou, Y, Kastritis, PL, Bonvin, AMJJ, Zhang, W, Camacho, CJ, Kilambi, KP, Sircar, A, Gray, JJ, Ohue, M, Uchikoga, N, Matsuzaki, Y, Ishida, T, Akiyama, Y, Khashan, R, Bush, S, Fouches, D, Tropsha, A, Esquivel-Rodríguez, J, Kihara, D, Stranges, PB, Jacak, R, Kuhlman, B, Huang, SY, Zou, X, Wodak, SJ, Janin, J & Baker, D 2011, 'Community-wide assessment of protein-interface modeling suggests improvements to design methodology' Journal of Molecular Biology, vol 414, no. 2, pp. 289-302. DOI: 10.1016/j.jmb.2011.09.031

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

In: Journal of Molecular Biology, Vol. 414, No. 2, 25.11.2011, p. 289-302.

Research output: Contribution to journalArticle

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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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AU - Whitehead,Timothy A.

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AU - Corn,Jacob E.

AU - Qin,Sanbo

AU - Zhou,Huan Xiang

AU - Mitchell,Julie C.

AU - Demerdash,Omar N A

AU - Takeda-Shitaka,Mayuko

AU - Terashi,Genki

AU - Moal,Iain H.

AU - Li,Xiaofan

AU - Bates,Paul A.

AU - Zacharias,Martin

AU - Park,Hahnbeom

AU - Ko,Jun Su

AU - Lee,Hasup

AU - Seok,Chaok

AU - Bourquard,Thomas

AU - Bernauer,Julie

AU - Poupon,Anne

AU - Azé,Jérôme

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AU - Pierce,Brian G.

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AU - Pons,Carles

AU - Fernández-Recio,Juan

AU - Jiang,Fan

AU - Yang,Feng

AU - Gong,Xinqi

AU - Cao,Libin

AU - Xu,Xianjin

AU - Liu,Bin

AU - Wang,Panwen

AU - Li,Chunhua

AU - Wang,Cunxin

AU - Robert,Charles H.

AU - Guharoy,Mainak

AU - Liu,Shiyong

AU - Huang,Yangyu

AU - Li,Lin

AU - Guo,Dachuan

AU - Chen,Ying

AU - Xiao,Yi

AU - London,Nir

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AU - Schueler-Furman,Ora

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AU - Potapov,Vladimir

AU - Cohen,Mati

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AU - Tsuchiya,Yuko

AU - Kanamori,Eiji

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AU - Hsu,Victor L.

AU - Zhan,Jian

AU - Yang,Yuedong

AU - Zhou,Yaoqi

AU - Kastritis,Panagiotis L.

AU - Bonvin,Alexandre M J J

AU - Zhang,Weiyi

AU - Camacho,Carlos J.

AU - Kilambi,Krishna P.

AU - Sircar,Aroop

AU - Gray,Jeffrey J.

AU - Ohue,Masahito

AU - Uchikoga,Nobuyuki

AU - Matsuzaki,Yuri

AU - Ishida,Takashi

AU - Akiyama,Yutaka

AU - Khashan,Raed

AU - Bush,Stephen

AU - Fouches,Denis

AU - Tropsha,Alexander

AU - Esquivel-Rodríguez,Juan

AU - Kihara,Daisuke

AU - Stranges,P. Benjamin

AU - Jacak,Ron

AU - Kuhlman,Brian

AU - Huang,Sheng You

AU - Zou,Xiaoqin

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AU - Janin,Joel

AU - Baker,David

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KW - conformational plasticity

KW - negative design

KW - protein-protein interactions

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