title: Computational Design of the Tiam1 PDZ Domain and Its Ligand Binding.
abstract: PDZ domains direct protein-protein interactions and serve as models for protein design. Here, we optimized a protein design energy function for the Tiam1 and Cask PDZ domains that combines a molecular mechanics energy, Generalized Born solvent, and an empirical unfolded state model. Designed sequences were recognized as PDZ domains by the Superfamily fold recognition tool and had similarity scores comparable to natural PDZ sequences. The optimized model was used to redesign the two PDZ domains, by gradually varying the chemical potential of hydrophobic amino acids; the tendency of each position to lose or gain a hydrophobic character represents a novel hydrophobicity index. We also redesigned four positions in the Tiam1 PDZ domain involved in peptide binding specificity. The calculated affinity differences between designed variants reproduced experimental data and suggest substitutions with altered specificities.
authors.affiliation: Laboratoire de Biochimie (CNRS UMR7654), Ecole Polytechnique , Palaiseau, France.
authors.forename: David
authors.initials: D
authors.lastname: Mignon
authors.affiliation: Laboratoire de Biochimie (CNRS UMR7654), Ecole Polytechnique , Palaiseau, France.
authors.forename: Nicolas
authors.identifier: http://orcid.org/0000-0001-8782-0586
authors.initials: N
authors.lastname: Panel
authors.affiliation: Laboratoire de Biochimie (CNRS UMR7654), Ecole Polytechnique , Palaiseau, France.
authors.forename: Xingyu
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Biochemistry, Roy J. & Lucille A. Carver College of Medicine and Holden Comprehensive Cancer Center, University of Iowa , Iowa City, Iowa 52242-1109, United States.
authors.forename: Ernesto J
authors.initials: EJ
authors.lastname: Fuentes
authors.affiliation: Laboratoire de Biochimie (CNRS UMR7654), Ecole Polytechnique , Palaiseau, France.
authors.forename: Thomas
authors.identifier: http://orcid.org/0000-0002-5117-7338
authors.initials: T
authors.lastname: Simonson
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D051528:Guanylate Kinases / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008024:Ligands; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D009010:Monte Carlo Method; D054731:PDZ Domains; D011485:Protein Binding; D017510:Protein Folding; D016415:Sequence Alignment; D000075684:T-Lymphoma Invasion and Metastasis-inducing Protein 1 / Q000737:chemistry* / Q000378:metabolism; D013816:Thermodynamics
chemical_list: D008024:Ligands; D000075684:T-Lymphoma Invasion and Metastasis-inducing Protein 1; C106868:CASK kinases; D051528:Guanylate Kinases