dc.contributor.author | Polydorides, Savvas | en |
dc.contributor.author | Amara, Najette | en |
dc.contributor.author | Aubard, C. | en |
dc.contributor.author | Plateau, P. | en |
dc.contributor.author | Simonson, T. | en |
dc.contributor.author | Archontis, Georgios Z. | en |
dc.creator | Polydorides, Savvas | en |
dc.creator | Amara, Najette | en |
dc.creator | Aubard, C. | en |
dc.creator | Plateau, P. | en |
dc.creator | Simonson, T. | en |
dc.creator | Archontis, Georgios Z. | en |
dc.date.accessioned | 2019-12-02T15:32:27Z | |
dc.date.available | 2019-12-02T15:32:27Z | |
dc.date.issued | 2011 | |
dc.identifier.uri | http://gnosis.library.ucy.ac.cy/handle/7/59010 | |
dc.description.abstract | 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. | en |
dc.source | Proteins: Structure, Function and Bioinformatics | en |
dc.source.uri | https://www.scopus.com/inward/record.uri?eid=2-s2.0-81055158020&doi=10.1002%2fprot.23042&partnerID=40&md5=8a8d31c5e364e61445bc890d05ca47b6 | |
dc.subject | article | en |
dc.subject | human | en |
dc.subject | priority journal | en |
dc.subject | amino acid sequence | en |
dc.subject | Computational Biology | en |
dc.subject | protein analysis | en |
dc.subject | binding affinity | en |
dc.subject | protein function | en |
dc.subject | protein interaction | en |
dc.subject | Point Mutation | en |
dc.subject | energy yield | en |
dc.subject | Ligands | en |
dc.subject | amino acid | en |
dc.subject | Molecular dynamics simulations | en |
dc.subject | molecular dynamics | en |
dc.subject | Protein Binding | en |
dc.subject | Protein Conformation | en |
dc.subject | protein stability | en |
dc.subject | adenosine triphosphate | en |
dc.subject | Protein Structure, Tertiary | en |
dc.subject | Binding Sites | en |
dc.subject | Amino Acids | en |
dc.subject | Substrate Specificity | en |
dc.subject | Models, Molecular | en |
dc.subject | Molecular Dynamics Simulation | en |
dc.subject | Aspartate-tRNA Ligase | en |
dc.subject | adenylation | en |
dc.subject | Aminoacyl-tRNA synthetases | en |
dc.subject | Genetic code | en |
dc.subject | Protein-ligand interactions | en |
dc.subject | Asparaginyl-tRNA synthetase | en |
dc.subject | Computational protein design | en |
dc.subject | Generalized Born model | en |
dc.subject | Implicit solvent models | en |
dc.subject | Poisson Boltzmann calculations | en |
dc.subject | Protein Folding | en |
dc.subject | RNA, Transfer, Amino Acyl | en |
dc.subject | Tyrosine-tRNA Ligase | en |
dc.title | Computational protein design with a generalized born solvent model: Application to asparaginyl-tRNA synthetase | en |
dc.type | info:eu-repo/semantics/article | |
dc.identifier.doi | 10.1002/prot.23042 | |
dc.description.volume | 79 | |
dc.description.issue | 12 | |
dc.description.startingpage | 3448 | |
dc.description.endingpage | 3468 | |
dc.author.faculty | Σχολή Θετικών και Εφαρμοσμένων Επιστημών / Faculty of Pure and Applied Sciences | |
dc.author.department | Τμήμα Φυσικής / Department of Physics | |
dc.type.uhtype | Article | en |
dc.description.notes | <p>Cited By :12</p> | en |
dc.source.abbreviation | Proteins Struct.Funct.Bioinformatics | en |
dc.contributor.orcid | Archontis, Georgios Z. [0000-0002-7750-8641] | |
dc.gnosis.orcid | 0000-0002-7750-8641 | |