A physical model for PDZ-domain/peptide interactions

The PDZ domain is an interaction motif that recognizes and binds the C-terminal peptides of target proteins. PDZ domains are ubiquitous in nature and help assemble multiprotein complexes that control cellular organization and signaling cascades. We present an optimized energy function to predict the binding free energy (ΔΔG) of PDZ domain/peptide interactions computationally. Geometry-optimized models of PDZ domain/peptide interfaces were built using Rosetta, and protein and peptide side chain and backbone degrees of freedom are minimized simultaneously. Using leave-one-out cross-validation, Rosetta’s energy function is adjusted to reproduce experimentally determined ΔΔG values with a correlation coefficient of 0.66 and a standard deviation of 0.79 kcal mol−1. The energy function places an increased weight on hydrogen bonding interactions when compared to a previously developed method to analyze protein/protein interactions. Binding free enthalpies (ΔΔH) and entropies (ΔS) are predicted with reduced accuracies of R = 0.60 and R = 0.17, respectively. The computational method improves prediction of PDZ domain specificity from sequence and allows design of novel PDZ domain/peptide interactions.

[1]  Chris Sander,et al.  A Specificity Map for the PDZ Domain Family , 2008, PLoS biology.

[2]  Jiunn R Chen,et al.  PDZ Domain Binding Selectivity Is Optimized Across the Mouse Proteome , 2007, Science.

[3]  D. Baker,et al.  An orientation-dependent hydrogen bonding potential improves prediction of specificity and structure for proteins and protein-protein complexes. , 2003, Journal of molecular biology.

[4]  B. Volkman,et al.  Cdc42 regulates the Par-6 PDZ domain through an allosteric CRIB-PDZ transition. , 2004, Molecular cell.

[5]  M. Karplus,et al.  Effective energy function for proteins in solution , 1999, Proteins.

[6]  Jacek Otlewski,et al.  PDZ tandem of human syntenin: crystal structure and functional properties. , 2003, Structure.

[7]  Yi Zhang,et al.  Structures of a Human Papillomavirus (HPV) E6 Polypeptide Bound to MAGUK Proteins: Mechanisms of Targeting Tumor Suppressors by a High-Risk HPV Oncoprotein , 2007, Journal of Virology.

[8]  D. Bredt,et al.  PDZ domain of neuronal nitric oxide synthase recognizes novel C-terminal peptide sequences , 1997, Nature Biotechnology.

[9]  John H. Lewis,et al.  Crystal Structures of a Complexed and Peptide-Free Membrane Protein–Binding Domain: Molecular Basis of Peptide Recognition by PDZ , 1996, Cell.

[10]  D. Baker,et al.  A simple physical model for binding energy hot spots in protein–protein complexes , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[11]  M. Sheng,et al.  PDZ Domains: Structural Modules for Protein Complex Assembly* , 2002, The Journal of Biological Chemistry.

[12]  David E. Kim,et al.  Computational Alanine Scanning of Protein-Protein Interfaces , 2004, Science's STKE.

[13]  Yi Liu,et al.  RosettaDesign server for protein design , 2006, Nucleic Acids Res..

[14]  Roland L. Dunbrack,et al.  Backbone-dependent rotamer library for proteins. Application to side-chain prediction. , 1993, Journal of molecular biology.

[15]  Seong-Hwan Rho,et al.  Crystal Structure of GRIP1 PDZ6-Peptide Complex Reveals the Structural Basis for Class II PDZ Target Recognition and PDZ Domain-mediated Multimerization* , 2003, The Journal of Biological Chemistry.

[16]  T. Pawson,et al.  Signaling through scaffold, anchoring, and adaptor proteins. , 1997, Science.

[17]  M. Sheng,et al.  PDZ domain proteins of synapses , 2004, Nature Reviews Neuroscience.

[18]  David R Cooper,et al.  Molecular roots of degenerate specificity in syntenin's PDZ2 domain: reassessment of the PDZ recognition paradigm. , 2003, Structure.

[19]  A. Annila,et al.  Peptide binding and NMR analysis of the interaction between SAP97 PDZ2 and GluR-A: potential involvement of a disulfide bond. , 2006, Biochemistry.

[20]  B. Stoddard,et al.  Design, activity, and structure of a highly specific artificial endonuclease. , 2002, Molecular cell.

[21]  Peer Bork,et al.  SMART: a web-based tool for the study of genetically mobile domains , 2000, Nucleic Acids Res..

[22]  P. Bradley,et al.  Toward High-Resolution de Novo Structure Prediction for Small Proteins , 2005, Science.

[23]  K. Dev,et al.  Making protein interactions druggable: targeting PDZ domains , 2004, Nature Reviews Drug Discovery.

[24]  A. Goldman,et al.  Crystal structure of the second PDZ domain of SAP97 in complex with a GluR‐A C‐terminal peptide , 2006, The FEBS journal.

[25]  D. Baker,et al.  Native protein sequences are close to optimal for their structures. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[26]  D. Baker,et al.  Computational redesign of protein-protein interaction specificity , 2004, Nature Structural &Molecular Biology.

[27]  C P Ponting,et al.  Evidence for PDZ domains in bacteria, yeast, and plants , 1997, Protein science : a publication of the Protein Society.

[28]  Yanxiang Zhao,et al.  Supramodular nature of GRIP1 revealed by the structure of its PDZ12 tandem in complex with the carboxyl tail of Fras1. , 2008, Journal of molecular biology.

[29]  Gavin MacBeath,et al.  Predicting PDZ domain–peptide interactions from primary sequences , 2008, Nature Biotechnology.

[30]  David Baker,et al.  Recapitulation and design of protein binding peptide structures and sequences. , 2006, Journal of molecular biology.

[31]  C. Kurschner,et al.  Neuronal Interleukin-16 (NIL-16): A Dual Function PDZ Domain Protein , 1999, The Journal of Neuroscience.

[32]  Seth G. N. Grant,et al.  PDZ Domain Proteins: Plug and Play! , 2003, Science's STKE.

[33]  Jolanta Grembecka,et al.  The binding of the PDZ tandem of syntenin to target proteins. , 2006, Biochemistry.

[34]  Jeffrey J. Gray,et al.  Protein-protein docking with simultaneous optimization of rigid-body displacement and side-chain conformations. , 2003, Journal of molecular biology.

[35]  Nicole Caspers,et al.  A thermodynamic ligand binding study of the third PDZ domain (PDZ3) from the mammalian neuronal protein PSD-95. , 2007, Biochemistry.