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Zeller, Fabian; Zacharias, Martin

Efficient calculation of relative binding free energies by umbrella sampling perturbation

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  • Medientyp: E-Artikel
  • Titel: Efficient calculation of relative binding free energies by umbrella sampling perturbation
  • Beteiligte: Zeller, Fabian; Zacharias, Martin
  • Erschienen: Wiley, 2014
  • Erschienen in: Journal of Computational Chemistry, 35 (2014) 31, Seite 2256-2262
  • Sprache: Englisch
  • DOI: 10.1002/jcc.23744
  • ISSN: 0192-8651; 1096-987X
  • Schlagwörter: Computational Mathematics ; General Chemistry
  • Entstehung:
  • Anmerkungen:
  • Beschreibung: <jats:p>An important task of biomolecular simulation is the calculation of relative binding free energies upon chemical modification of partner molecules in a biomolecular complex. The potential of mean force (PMF) along a reaction coordinate for association or dissociation of the complex can be used to estimate binding affinities. A free energy perturbation approach, termed umbrella sampling (US) perturbation, has been designed that allows an efficient calculation of the change of the PMF upon modification of a binding partner based on the trajectories obtained for the wild type reference complex. The approach was tested on the interaction of modified water molecules in aqueous solution and applied to <jats:italic>in silico</jats:italic> alanine scanning of a peptide‐protein complex. For the water interaction test case, excellent agreement with an explicit PMF calculation for each modification was obtained as long as no long range electrostatic perturbations were considered. For the alanine scanning, the experimentally determined ranking and binding affinity changes upon alanine substitutions could be reproduced within 0.1–2.0 kcal/mol. In addition, good agreement with explicitly calculated PMFs was obtained mostly within the sampling uncertainty. The combined US and perturbation approach yields, under the condition of sufficiently small system modifications, rigorously derived changes in free energy and is applicable to any PMF calculation. © 2014 Wiley Periodicals, Inc.</jats:p>