Computational protein design with a generalized born solvent model: Application to asparaginyl-tRNA synthetase
Autor: | Polydorides, Savvas, Amara, Najette, Aubard, C., Plateau, P., Simonson, T., Archontis, Georgios Z. |
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Přispěvatelé: | Department of Physics, Laboratoire de Biochimie de l'Ecole polytechnique (BIOC), École polytechnique (X)-Centre National de la Recherche Scientifique (CNRS), Archontis, Georgios Z. [0000-0002-7750-8641] |
Rok vydání: | 2011 |
Předmět: |
Models
Molecular Protein Folding MESH: Amino Acids Implicit solvent models Protein Conformation Genetic code Aspartate-tRNA Ligase Protein-ligand interactions MESH: Amino Acid Sequence RNA Transfer Amino Acyl Ligands Biochemistry Substrate Specificity MESH: Protein Structure Tertiary chemistry.chemical_compound MESH: Protein Conformation Protein structure Tyrosine-tRNA Ligase Structural Biology binding affinity MESH: Ligands MESH: Molecular Dynamics Simulation Amino Acids article protein function Poisson Boltzmann calculations priority journal protein stability adenylation Protein folding Computational protein design amino acid MESH: Models Molecular Protein Binding MESH: Computational Biology MESH: Protein Folding adenosine triphosphate Protein design Molecular Dynamics Simulation Accessible surface area Protein–protein interaction Aminoacyl-tRNA synthetases MESH: RNA Transfer Amino Acyl MESH: Tyrosine-tRNA Ligase Point Mutation MESH: Protein Binding [SDV.BBM]Life Sciences [q-bio]/Biochemistry Molecular Biology human protein interaction Amino Acid Sequence MESH: Aspartate-tRNA Ligase Binding site Molecular Biology MESH: Point Mutation Binding Sites Generalized Born model Molecular dynamics simulations Aminoacyl tRNA synthetase Computational Biology molecular dynamics amino acid sequence Protein Structure Tertiary Crystallography MESH: Binding Sites chemistry protein analysis MESH: Substrate Specificity Solvent effects Asparaginyl-tRNA synthetase energy yield |
Zdroj: | Proteins-Structure, Function and Bioinformatics Proteins-Structure, Function and Bioinformatics, Wiley, 2011, 79 (12), pp.3448-68. ⟨10.1002/prot.23042⟩ Proteins: Structure, Function and Bioinformatics Proteins Struct.Funct.Bioinformatics |
ISSN: | 0887-3585 1097-0134 |
DOI: | 10.1002/prot.23042 |
Popis: | Computational Protein Design (CPD) is a promising method for high throughput protein and ligand mutagenesis. Recently, we developed a CPD method that used a polar-hydrogen energy function for protein interactions and a Coulomb/Accessible Surface Area (CASA) model for solvent effects. We applied this method to engineer aspartyl-adenylate (AspAMP) specificity into Asparaginyl-tRNA synthetase (AsnRS), whose substrate is asparaginyl-adenylate (AsnAMP). Here, we implement a more accurate function, with an all-atom energy for protein interactions and a residue-pairwise generalized Born model for solvent effects. As a first test, we compute aminoacid affinities for several point mutants of Aspartyl-tRNA synthetase (AspRS) and Tyrosyl-tRNA synthetase and stability changes for three helical peptides and compare with experiment. As a second test, we readdress the problem of AsnRS aminoacid engineering. We compare three design criteria, which optimize the folding free-energy, the absolute AspAMP affinity, and the relative (AspAMP-AsnAMP) affinity. The sequences and conformations are improved with respect to our previous, polar-hydrogen/CASA study: For several designed complexes, the AspAMP carboxylate forms three interactions with a conserved arginine and a designed lysine, as in the active site of the AspRS:AspAMP complex. The conformations and interactions are well maintained in molecular dynamics simulations and the sequences have an inverted specificity, favoring AspAMP over AsnAMP. The method is not fully successful, since experimental measurements with the seven most promising sequences show that they do not catalyze at a detectable level the adenylation of Asp (or Asn) with ATP. This may be due to weak AspAMP binding and/or disruption of transition-state stabilization. © 2011 Wiley-Liss, Inc. 79 12 3448 3468 Cited By :12 |
Databáze: | OpenAIRE |
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