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The accurate prediction of protein-ligand binding affinities is crucial for drug discovery. Alchemical free energy calculations have become a popular tool for this purpose. However, the accuracy and reliability of these methods can vary depending on the methodology. In this study, we evaluate the performance of a relative binding free energy protocol based on the alchemical transfer method (ATM), a novel approach based on a coordinate transformation that swaps the positions of two ligands. The results show that ATM matches the performance of more complex free energy perturbation (FEP) methods in terms of Pearson correlation, but with marginally higher mean absolute errors. This study shows that the ATM method is competitive compared to more traditional methods in speed and accuracy and offers the advantage of being applicable with any potential energy function.
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Alchemical Transformations for Single-Step Hydration Free Energy Calculations
We present a family of alchemical perturbation potentials that allow the calculation of hydration free energy of small to medium-sized molecules in a single perturbation step. We also present a general framework to optimize the parameters of the alchemical perturbation potentials based on avoiding first order pseudo phase transitions along the alchemical path. We illustrate the method for two compounds of increasing size and complexity: ethanol and 1-naphthol. In each case we show that convergence of the hydration free energy is achieved rapidly when conventional approaches fail.
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- Award ID(s):
- 1750511
- PAR ID:
- 10173030
- Date Published:
- Journal Name:
- ArXivorg
- Volume:
- 2005.06504
- ISSN:
- 2331-8422
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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