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Article

Accurate Receptor-Ligand Binding Free Energies from Fast QM Conformational Chemical Space Sampling

Max Planck Institute for Dynamics of Complex Technical Systems, Molecular Simulations and Design Group, 39106 Magdeburg, Germany
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Academic Editor: Alexander Baykov
Int. J. Mol. Sci. 2021, 22(6), 3078; https://doi.org/10.3390/ijms22063078
Received: 15 February 2021 / Revised: 13 March 2021 / Accepted: 15 March 2021 / Published: 17 March 2021
(This article belongs to the Section Molecular Biophysics)
Small molecule receptor-binding is dominated by weak, non-covalent interactions such as van-der-Waals hydrogen bonding or electrostatics. Calculating these non-covalent ligand-receptor interactions is a challenge to computational means in terms of accuracy and efficacy since the ligand may bind in a number of thermally accessible conformations. The conformational rotamer ensemble sampling tool (CREST) uses an iterative scheme to efficiently sample the conformational space and calculates energies using the semi-empirical ‘Geometry, Frequency, Noncovalent, eXtended Tight Binding’ (GFN2-xTB) method. This combined approach is applied to blind predictions of the modes and free energies of binding for a set of 10 drug molecule ligands to the cucurbit[n]urils CB[8] receptor from the recent ‘Statistical Assessment of the Modeling of Proteins and Ligands’ (SAMPL) challenge including morphine, hydromorphine, cocaine, fentanyl, and ketamine. For each system, the conformational space was sufficiently sampled for the free ligand and the ligand-receptor complexes using the quantum chemical Hamiltonian. A multitude of structures makes up the final conformer-rotamer ensemble, for which then free energies of binding are calculated. For those large and complex molecules, the results are in good agreement with experimental values with a mean error of 3 kcal/mol. The GFN2-xTB energies of binding are validated by advanced density functional theory calculations and found to be in good agreement. The efficacy of the automated QM sampling workflow allows the extension towards other complex molecular interaction scenarios. View Full-Text
Keywords: ligand binding free energy; DFT; conformational sampling; ligand-receptor binding; GFN2-xTB; conformational entropy ligand binding free energy; DFT; conformational sampling; ligand-receptor binding; GFN2-xTB; conformational entropy
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MDPI and ACS Style

Boz, E.; Stein, M. Accurate Receptor-Ligand Binding Free Energies from Fast QM Conformational Chemical Space Sampling. Int. J. Mol. Sci. 2021, 22, 3078. https://doi.org/10.3390/ijms22063078

AMA Style

Boz E, Stein M. Accurate Receptor-Ligand Binding Free Energies from Fast QM Conformational Chemical Space Sampling. International Journal of Molecular Sciences. 2021; 22(6):3078. https://doi.org/10.3390/ijms22063078

Chicago/Turabian Style

Boz, Esra, and Matthias Stein. 2021. "Accurate Receptor-Ligand Binding Free Energies from Fast QM Conformational Chemical Space Sampling" International Journal of Molecular Sciences 22, no. 6: 3078. https://doi.org/10.3390/ijms22063078

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