Get access

Computational prediction and analysis of the DR6–NAPP interaction

Authors

  • Sergei Y. Ponomarev,

    1. CMD Bioscience, LLC, 554 Boston Post Rd #318, Orange, Connecticut 06477
    Search for more papers by this author
    • Sergei Y. Ponomarev and Joseph Audie contributed equally to this work.

  • Joseph Audie

    Corresponding author
    1. CMD Bioscience, LLC, 554 Boston Post Rd #318, Orange, Connecticut 06477
    2. Department of Chemistry, Sacred Heart University, 5151 Park Ave, Fairfield, Connecticut 06825
    • Department of Chemistry, Sacred Heart University, 5151 Park Ave, Fairfield, Connecticut 06825
    Search for more papers by this author
    • Sergei Y. Ponomarev and Joseph Audie contributed equally to this work.


  • Conflict of interest: J.A. is a cofounder of CMDBioscience.

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that involves a devastating clinical course and that lacks an effective treatment. A biochemical model for neuronal development, recently proposed by Nikolaev et al., that may also have implications for AD, hinges on a novel protein–protein interaction between the death cell receptor 6 (DR6) ectodomain and an N-terminal fragment of amyloid precursor protein (NAPP), specifically, the growth factor-like domain of NAPP (GFD NAPP). Given all of this, we used a pure computational work-flow to dock a binding competent homology model of the DR6 ectodomain to a binding competent crystal structure of GFD NAPP. The DR6 homology model was built according to a template supplied by the neurotrophin p75 receptor. The best docked model was selected according to an empirical estimate of the binding affinity and represents a high quality model of probable structural accuracy, especially with respect to the residue-level contribution of GFD NAPP. The final model was tested and verified against a variety of biophysical and theoretical data sets. Particularly, worth noting is the excellent observed agreement between the theoretically calculated DR6–GFD NAPP binding free energy and the experimental quantity. The model is used to provide a satisfying structural and energetic interpretation of DR6–GFD NAPP binding and to suggest the possibility of and a mechanism for spontaneous apoptosis. The evidence suggests that the DR6–NAPP model proposed here is of probable accuracy and that it will prove useful in future studies, modeling work, and structure-based AD drug design. Proteins 2011. © 2010 Wiley-Liss, Inc.

Get access to the full text of this article

Ancillary