Characterization of PDZ domain-peptide interaction interface based on energetic patterns

Authors

  • Nan Li,

    1. Department of Chemistry and Biochemisty, University of California, San Diego, La Jolla, California
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  • Tingjun Hou,

    1. Institute of Functional Nano and Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Soochow University, Suzhou, Jiangsu, People's Republic of China
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  • Bo Ding,

    1. Department of Chemistry and Biochemisty, University of California, San Diego, La Jolla, California
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  • Wei Wang

    Corresponding author
    1. Department of Chemistry and Biochemisty, University of California, San Diego, La Jolla, California
    • Correspondence to: Wei Wang, Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0359. E-mail: wei-wang@ucsd.edu

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Errata

This article corrects:

  1. Block-adaptive quantum mechanics: An adaptive divide-and-conquer approach to interactive quantum chemistry Volume 34, Issue 6, 492–504, Article first published online: 29 October 2012

ABSTRACT

PDZ domain is one of the abundant modular domains that recognize short peptide sequences to mediate protein–protein interactions. To decipher the binding specificity of PDZ domain, we analyzed the interactions between 11 mouse PDZ domains and 217 peptides using a method called MIECSVM, which energetically characterizes the domain-peptide interaction using molecular interaction energy components (MIECs) and predicts binding specificity using support vector machine (SVM). Cross-validation and leave-one-domain-out test showed that the MIEC-SVM using all 44 PDZ-peptide residue pairs at the interaction interface outperformed the sequence-based methods in the literature. A further feature (residue pair) selection procedure illustrated that 16 residue pairs were uninformative to the binding specificity, even though they contributed significantly (∼50%) to the binding energy. If only using the 28 informative residue pairs, the performance of the MIEC-SVM on predicting the PDZ binding specificity was significantly improved. This analysis suggests that the informative and uninformative residue interactions between the PDZ domain and the peptide may represent those contributing to binding specificity and affinity, respectively. We performed additional structural and energetic analyses to shed light on understanding how the PDZ-peptide recognition is established. The success of the MIEC-SVM method on PDZ domains in this study and SH3 domains in our previous studies illustrates its generality on characterizing protein- peptide interactions and understanding protein recognition from a structural and energetic viewpoint.

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