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

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.

SUBMITTER: Fleishman SJ

PROVIDER: S-EPMC3839241 | biostudies-literature | 2011 Nov

REPOSITORIES: biostudies-literature

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

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

Journal of molecular biology 20110929 2

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 fundame ...[more]

PMID: 22001016

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Project description:The major advances in molecular and structural biology and automated peptide and DNA synthesis of the 1970s and 1980s generated fertile conditions in the 1990s for the exploration of designed proteins as a new approach for inorganic chemists to generate biomolecular mimics of metalloproteins. This Account follows the development of the TRI peptide family of three-stranded coiled coils (3SCC) and ?3D family of three-helix bundles (3HB) as scaffolds for the preparation of metal binding sites within de novo designed constructs. The 3SCC were developed using the concept of a heptad repeat (abcdefg) putting hydrophobes in the a and d positions. The TRI peptides contain four heptads with capping glycines. Via substitution of leucine hydrophobes, metal ligands can be introduced into the a or d sites in order to bind metals. First, the ability to use cysteine-substituted 3SCC aggregates to impose higher or lower coordination numbers on Hg(II) and Cd(II) or matching the coordination preferences of As(III) and Pb(II) is discussed. Then, methods to develop dual site peptides capable of discriminating metals based on their type (e.g., Cd(II) vs Pb(II)), their preference for a vs d sites, and then their coordination number is described. Once these principles of metal site differentiation are described, we shift to building dual site peptides using both cysteine and histidine metal binding sites. This approach provides a construct with both a Hg(II) structural and a Zn(II) hydrolytic center, the latter of which is capable of hydrating CO2. With these Zn(II) proteins, we consider the relative importance of the location of the catalytic center along the primary sequence of the peptide and show that only minor perturbations in catalytic efficiencies are observed based on metal location. We then assess the feasibility of preparing enzymes competent to reduce nitrite with copper centers in a histidine-rich environment. As part of this discussion, we examine the influence of surface residues on catalyst reduction potentials and catalytic efficiencies. We end describing approaches to prepare asymmetric proteins that can incorporate acid-base catalysts or water channels. In this respect, we highlight modifications of a helix-turn-helix-turn-helix motif called ?3D and show how this 3HB can be modified to bind heavy metals or to make Zn(II) centers, which are active hydrolytic catalysts. A comparison is made to the comparable parallel 3SCC.

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

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

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