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Triathlon for energy functions: Who is the winner for design of protein–protein interactions?

Authors

  • Oz Sharabi,

    1. Department of Biological Chemistry, The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 91904, Israel
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  • Ayelet Dekel,

    1. Department of Biological Chemistry, The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 91904, Israel
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  • Julia M. Shifman

    Corresponding author
    1. Department of Biological Chemistry, The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 91904, Israel
    • Department of Biological Chemistry, The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 91904, Israel
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Abstract

Computational prediction of stabilizing mutations into monomeric proteins has become an almost ordinary task. Yet, computational stabilization of protein–protein complexes remains a challenge. Design of protein–protein interactions (PPIs) is impeded by the absence of an energy function that could reliably reproduce all favorable interactions between the binding partners. In this work, we present three energy functions: one function that was trained on monomeric proteins, while the other two were optimized by different techniques to predict side-chain conformations in a dataset of PPIs. The performances of these energy functions are evaluated in three different tasks related to design of PPIs: predicting side-chain conformations in PPIs, recovering native binding-interface sequences, and predicting changes in free energy of binding due to mutations. Our findings show that both functions optimized on side-chain repacking in PPIs are more suitable for PPI design compared to the function trained on monomeric proteins. Yet, no function performs best at all three tasks. Comparison of the three energy functions and their performances revealed that (1) burial of polar atoms should not be penalized significantly in PPI design as in single-protein design and (2) contribution of electrostatic interactions should be increased several-fold when switching from single-protein to PPI design. In addition, the use of a softer van der Waals potential is beneficial in cases when backbone flexibility is important. All things considered, we define an energy function that captures most of the nuances of the binding energetics and hence, should be used in future for design of PPIs. Proteins 2011; © 2011 Wiley-Liss, Inc.

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