Protein:Ligand binding free energies: A stringent test for computational protein design

Abstract : 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. © 2015 Wiley Periodicals, Inc.
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Article dans une revue
Journal of Computational Chemistry, Wiley, 2016, 37 (4), pp.404-415. 〈10.1002/jcc.24230〉
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Soumis le : jeudi 18 février 2016 - 20:23:14
Dernière modification le : jeudi 10 mai 2018 - 02:08:10

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Karen Druart, Zoltan Palmai, Eyaz Omarjee, Thomas Simonson. Protein:Ligand binding free energies: A stringent test for computational protein design. Journal of Computational Chemistry, Wiley, 2016, 37 (4), pp.404-415. 〈10.1002/jcc.24230〉. 〈hal-01276168〉

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