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231224s2016 xx |||||o 00| ||eng c |
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|a 10.1002/jcc.24230
|2 doi
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|a pubmed24n0846.xml
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|a (DE-627)NLM254040047
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|a (NLM)26503829
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|a DE-627
|b ger
|c DE-627
|e rakwb
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|a eng
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| 100 |
1 |
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|a Druart, Karen
|e verfasserin
|4 aut
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| 245 |
1 |
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|a Protein:Ligand binding free energies
|b A stringent test for computational protein design
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|c 2016
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|a Text
|b txt
|2 rdacontent
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|a ƒaComputermedien
|b c
|2 rdamedia
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|a ƒa Online-Ressource
|b cr
|2 rdacarrier
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|a Date Completed 20.09.2016
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|a Date Revised 08.01.2016
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|a published: Print-Electronic
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|a Citation Status MEDLINE
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|a © 2015 Wiley Periodicals, Inc.
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|a A computational protein design method is extended to allow Monte Carlo simulations where two ligands are titrated into a protein binding pocket, yielding binding free energy differences. These provide a stringent test of the physical model, including the energy surface and sidechain rotamer definition. As a test, we consider tyrosyl-tRNA synthetase (TyrRS), which has been extensively redesigned experimentally. We consider its specificity for its substrate l-tyrosine (l-Tyr), compared to the analogs d-Tyr, p-acetyl-, and p-azido-phenylalanine (ac-Phe, az-Phe). We simulate l- and d-Tyr binding to TyrRS and six mutants, and compare the structures and binding free energies to a more rigorous "MD/GBSA" procedure: molecular dynamics with explicit solvent for structures and a Generalized Born + Surface Area model for binding free energies. Next, we consider l-Tyr, ac- and az-Phe binding to six other TyrRS variants. The titration results are sensitive to the precise rotamer definition, which involves a short energy minimization for each sidechain pair to help relax bad contacts induced by the discrete rotamer set. However, when designed mutant structures are rescored with a standard GBSA energy model, results agree well with the more rigorous MD/GBSA. As a third test, we redesign three amino acid positions in the substrate coordination sphere, with either l-Tyr or d-Tyr as the ligand. For two, we obtain good agreement with experiment, recovering the wildtype residue when l-Tyr is the ligand and a d-Tyr specific mutant when d-Tyr is the ligand. For the third, we recover His with either ligand, instead of wildtype Gln
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|a Journal Article
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|a Research Support, Non-U.S. Gov't
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|a aminoacyl-tRNA synthetase
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| 650 |
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|a continuum electrostatics
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|a molecular dynamics
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|a Ligands
|2 NLM
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|a Mutant Proteins
|2 NLM
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|a Tyrosine
|2 NLM
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| 650 |
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|a 42HK56048U
|2 NLM
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| 650 |
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|a Tyrosine-tRNA Ligase
|2 NLM
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| 650 |
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|a EC 6.1.1.1
|2 NLM
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| 700 |
1 |
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|a Palmai, Zoltan
|e verfasserin
|4 aut
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| 700 |
1 |
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|a Omarjee, Eyaz
|e verfasserin
|4 aut
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| 700 |
1 |
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|a Simonson, Thomas
|e verfasserin
|4 aut
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| 773 |
0 |
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|i Enthalten in
|t Journal of computational chemistry
|d 1984
|g 37(2016), 4 vom: 05. Feb., Seite 404-15
|w (DE-627)NLM098138448
|x 1096-987X
|7 nnns
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| 773 |
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|g volume:37
|g year:2016
|g number:4
|g day:05
|g month:02
|g pages:404-15
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|u http://dx.doi.org/10.1002/jcc.24230
|3 Volltext
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