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  Challenges encountered applying equilibrium and nonequilibrium binding free energy calculations

Baumann, H. M., Gapsys, V., de Groot, B. L., & Mobley, D. L. (2021). Challenges encountered applying equilibrium and nonequilibrium binding free energy calculations. Journal of Physical Chemistry B, 125(17), 4241-4261. doi:10.1021/acs.jpcb.0c10263.

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3332254.pdf (Publisher version), 9MB
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Baumann, H. M., Author
Gapsys, V.1, Author              
de Groot, B. L.1, Author              
Mobley, D. L., Author
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1Research Group of Computational Biomolecular Dynamics, MPI for biophysical chemistry, Max Planck Society, ou_578573              

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Free keywords: Free energy, Ligands, Chemical calculations, Screening assays, Computer simulations
 Abstract: Binding free energy calculations have become increasingly valuable to drive decision making in drug discovery projects. However, among other issues, inadequate sampling can reduce accuracy, limiting the value of the technique. In this paper, we apply absolute binding free energy calculations to ligands binding to T4 lysozyme L99A and HSP90 using equilibrium and nonequilibrium approaches. We highlight sampling problems encountered in these systems, such as slow side chain rearrangements and slow changes of water placement upon ligand binding. These same types of challenges are also likely to show up in other protein–ligand systems, and we propose some strategies to diagnose and test for such problems in alchemical free energy calculations. We also explore similarities and differences in how the equilibrium and the nonequilibrium approaches handle these problems. Our results show the large amount of work still to be done to make free energy calculations robust and reliable and provide insight for future research in this area.

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Language(s): eng - English
 Dates: 2021-04-27
 Publication Status: Published online
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 Rev. Type: Peer
 Identifiers: DOI: 10.1021/acs.jpcb.0c10263
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Title: Journal of Physical Chemistry B
Source Genre: Journal
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Pages: - Volume / Issue: 125 (17) Sequence Number: - Start / End Page: 4241 - 4261 Identifier: -