Computational design, construction, and characterization of a set of specificity determining residues in protein–protein interactions

Authors

  • Chioko Nagao,

    Corresponding author
    1. National Institute of Biomedical Innovation, Ibaraki, Osaka 567-0085, Japan
    • National Institute of Biomedical Innovation, 7-6-8 Saito-Asagi, Ibaraki, Osaka 567-0085, Japan
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  • Nozomi Izako,

    1. Molecular Medicine Research Labs., Drug Discovery Research, Astellas Pharma Inc., Tsukuba-Shi, Ibaraki 305-8585, Japan
    2. Hitachi Solutions, Ltd., Life Science Research Center, Tsurumi-Ku, Yokohama 230-0045, Japan
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  • Shinji Soga,

    1. Molecular Medicine Research Labs., Drug Discovery Research, Astellas Pharma Inc., Tsukuba-Shi, Ibaraki 305-8585, Japan
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  • Samia Haseeb Khan,

    1. National Institute of Biomedical Innovation, Ibaraki, Osaka 567-0085, Japan
    2. Graduate School of Frontier Biosciences, Osaka University, Suita, Osaka 565-0871, Japan
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  • Shigeki Kawabata,

    1. Molecular Medicine Research Labs., Drug Discovery Research, Astellas Pharma Inc., Tsukuba-Shi, Ibaraki 305-8585, Japan
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  • Hiroki Shirai,

    1. Molecular Medicine Research Labs., Drug Discovery Research, Astellas Pharma Inc., Tsukuba-Shi, Ibaraki 305-8585, Japan
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  • Kenji Mizuguchi

    1. National Institute of Biomedical Innovation, Ibaraki, Osaka 567-0085, Japan
    2. Graduate School of Frontier Biosciences, Osaka University, Suita, Osaka 565-0871, Japan
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Abstract

Proteins interact with different partners to perform different functions and it is important to elucidate the determinants of partner specificity in protein complex formation. Although methods for detecting specificity determining positions have been developed previously, direct experimental evidence for these amino acid residues is scarce, and the lack of information has prevented further computational studies. In this article, we constructed a dataset that is likely to exhibit specificity in protein complex formation, based on available crystal structures and several intuitive ideas about interaction profiles and functional subclasses. We then defined a “structure-based specificity determining position (sbSDP)” as a set of equivalent residues in a protein family showing a large variation in their interaction energy with different partners. We investigated sequence and structural features of sbSDPs and demonstrated that their amino acid propensities significantly differed from those of other interacting residues and that the importance of many of these residues for determining specificity had been verified experimentally. Proteins 2012;. © 2012 Wiley Periodicals, Inc.

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