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.
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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