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  Accurate absolute free energies for ligand-protein binding based on non-equilibrium approaches

Gapsys, V., Yildirim, A., Aldeghi, M., Khalak, Y., van der Spoel, D., & de Groot, B. L. (2021). Accurate absolute free energies for ligand-protein binding based on non-equilibrium approaches. Communications Chemistry, 4: 61. doi:10.1038/s42004-021-00498-y.

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Gapsys, V.1, Author              
Yildirim, A., Author
Aldeghi, M., Author
Khalak, Y2, Author              
van der Spoel, D., Author
de Groot, B. L.1, Author              
Affiliations:
1Research Group of Computational Biomolecular Dynamics, MPI for biophysical chemistry, Max Planck Society, ou_578573              
2Research Group of Computational Biomolecular Dynamics, MPI for Biophysical Chemistry, Max Planck Society, ou_578573              

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Free keywords: Computational chemistry; Molecular dynamics; Statistical mechanics; Structure-based drug design
 Abstract: The accurate calculation of the binding free energy for arbitrary ligand–protein pairs is a considerable challenge in computer-aided drug discovery. Recently, it has been demonstrated that current state-of-the-art molecular dynamics (MD) based methods are capable of making highly accurate predictions. Conventional MD-based approaches rely on the first principles of statistical mechanics and assume equilibrium sampling of the phase space. In the current work we demonstrate that accurate absolute binding free energies (ABFE) can also be obtained via theoretically rigorous non-equilibrium approaches. Our investigation of ligands binding to bromodomains and T4 lysozyme reveals that both equilibrium and non-equilibrium approaches converge to the same results. The non-equilibrium approach achieves the same level of accuracy and convergence as an equilibrium free energy perturbation (FEP) method enhanced by Hamiltonian replica exchange. We also compare uni- and bi-directional non-equilibrium approaches and demonstrate that considering the work distributions from both forward and reverse directions provides substantial accuracy gains. In summary, non-equilibrium ABFE calculations are shown to yield reliable and well-converged estimates of protein–ligand binding affinity.

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Language(s): eng - English
 Dates: 2021-05-11
 Publication Status: Published online
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 Table of Contents: -
 Rev. Type: Peer
 Identifiers: DOI: 10.1038/s42004-021-00498-y
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Title: Communications Chemistry
Source Genre: Journal
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Pages: 13 Volume / Issue: 4 Sequence Number: 61 Start / End Page: - Identifier: -