Sergei Y. Ponomarev and Joseph Audie contributed equally to this work.
Computational prediction and analysis of the DR6–NAPP interaction†
Article first published online: 18 FEB 2011
Copyright © 2010 Wiley-Liss, Inc.
Proteins: Structure, Function, and Bioinformatics
Volume 79, Issue 5, pages 1376–1395, May 2011
How to Cite
Ponomarev, S. Y. and Audie, J. (2011), Computational prediction and analysis of the DR6–NAPP interaction. Proteins, 79: 1376–1395. doi: 10.1002/prot.22962
Conflict of interest: J.A. is a cofounder of CMDBioscience.
- Issue published online: 12 APR 2011
- Article first published online: 18 FEB 2011
- Accepted manuscript online: 13 DEC 2010 04:39PM EST
- Manuscript Accepted: 24 NOV 2010
- Manuscript Revised: 2 NOV 2010
- Manuscript Received: 21 JUN 2010
- Alzheimer's disease;
- death cell receptor 6;
- N-terminal amyloid precursor protein;
- homology modeling;
- implicit solvent;
- structure refinement;
- energy minimization;
- rigid-body protein–protein docking;
- binding free energy;
- scoring and ranking
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.