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Design of a modified mouse protein with ligand binding properties of its human analog by molecular dynamics simulations: The case of C3 inhibition by compstatin

Authors

  • Phanourios Tamamis,

    1. Department of Physics, University of Cyprus, PO20537, CY1678, Nicosia, Cyprus
    2. Department of Chemical and Biological Engineering, Princeton University, Princeton, New Jersey 08544
    3. Department of Bioengineering, University of California, Riverside, California 92521
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    • Phanourios Tamamis is a Fulbright visiting Scholar at the University of California, Riverside and at Princeton University.

  • Panayiota Pierou,

    1. Department of Physics, University of Cyprus, PO20537, CY1678, Nicosia, Cyprus
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  • Chrystalla Mytidou,

    1. Department of Physics, University of Cyprus, PO20537, CY1678, Nicosia, Cyprus
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  • Christodoulos A. Floudas,

    Corresponding author
    1. Department of Chemical and Biological Engineering, Princeton University, Princeton, New Jersey 08544
    • Department of Chemical and Biological Engineering, Princeton University, Princeton, New Jersey 08544
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  • Dimitrios Morikis,

    Corresponding author
    1. Department of Bioengineering, University of California, Riverside, California 92521
    • Department of Bioengineering, University of California, Riverside, California 92521
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  • Georgios Archontis

    Corresponding author
    1. Department of Physics, University of Cyprus, PO20537, CY1678, Nicosia, Cyprus
    • Department of Physics, University of Cyprus, PO20537, CY1678, Nicosia, Cyprus
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Abstract

The peptide compstatin and its derivatives inhibit the complement-component protein C3 in primate mammals and are potential therapeutic agents against the unregulated activation of complement in humans, but are inactive against C3 from lower mammals. Recent molecular dynamics (MD) simulations showed that the most potent compstatin analog comprised entirely of natural amino acids (W4A9) had a smaller affinity for rat C3, due to reproducible changes in the rat protein structure with respect to the human protein, which eliminated or weakened specific protein–ligand interactions seen in the human C3:W4A9 complex. Here, we study by MD simulations three W4A9 complexes with the mouse C3 protein, and two “transgenic” mouse derivatives, containing a small number (6–9) of human C3 substitutions. The mouse complex experiences the conformational changes and affinity reduction of the rat complex. In the “transgenic” complexes, the conformation remains closer to that of the human complex, the protein–ligand interactions are improved, and the affinity for compstatin becomes “human-like.” The present work creates new avenues for a compstatin-sensitive animal model. A similar strategy, involving the comparison of a series of complexes by MD simulations, could be used to design “transgenic” sequences in other systems. Proteins 2011;. © 2011 Wiley-Liss, Inc.

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