Converging ligand-binding free energies obtained with free-energy perturbations at the quantum mechanical level
© 2016 The Authors. Journal of Computational Chemistry Published by Wiley Periodicals, Inc.
| Veröffentlicht in: | Journal of computational chemistry. - 1984. - 37(2016), 17 vom: 30. Juni, Seite 1589-600 |
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| Format: | Online-Aufsatz |
| Sprache: | English |
| Veröffentlicht: |
2016
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| Zugriff auf das übergeordnete Werk: | Journal of computational chemistry |
| Schlagworte: | Journal Article Research Support, Non-U.S. Gov't QM/MM free-energy perturbation host-guest systems ligand binding non-Boltzmann Bennett acceptance ratio method octa-acid host quantum mechanics semi-empirical methods single-step exponential averaging |
| Zusammenfassung: | © 2016 The Authors. Journal of Computational Chemistry Published by Wiley Periodicals, Inc. In this article, the convergence of quantum mechanical (QM) free-energy simulations based on molecular dynamics simulations at the molecular mechanics (MM) level has been investigated. We have estimated relative free energies for the binding of nine cyclic carboxylate ligands to the octa-acid deep-cavity host, including the host, the ligand, and all water molecules within 4.5 Å of the ligand in the QM calculations (158-224 atoms). We use single-step exponential averaging (ssEA) and the non-Boltzmann Bennett acceptance ratio (NBB) methods to estimate QM/MM free energy with the semi-empirical PM6-DH2X method, both based on interaction energies. We show that ssEA with cumulant expansion gives a better convergence and uses half as many QM calculations as NBB, although the two methods give consistent results. With 720,000 QM calculations per transformation, QM/MM free-energy estimates with a precision of 1 kJ/mol can be obtained for all eight relative energies with ssEA, showing that this approach can be used to calculate converged QM/MM binding free energies for realistic systems and large QM partitions. © 2016 The Authors. Journal of Computational Chemistry Published by Wiley Periodicals, Inc |
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| Beschreibung: | Date Completed 19.07.2018 Date Revised 26.03.2024 published: Print-Electronic Citation Status PubMed-not-MEDLINE |
| ISSN: | 1096-987X |
| DOI: | 10.1002/jcc.24375 |