Calculated hydration free energies become less accurate with increases in molecular weight

25 March 2024, Version 1
This content is a preprint and has not undergone peer review at the time of posting.


In order for computer-aided drug design to fulfil its long held promise of delivering new medicines faster and cheaper, extensive development and validation work must be done first. This pertains particularly to molecular dynamics force fields where one important aspect – the hydration free energy (HFE) of small molecules – is often insufficiently and deceptively analyzed and reported. While most benchmarking studies report excellent accuracies of calculated hydration free energies – usually within 2 kcal/mol of the experimental values – we find that deeper analysis reveals significant shortcomings. Herein, we report a dependence of HFE prediction errors on ligand molecular weight – the higher the weight, the bigger the prediction error and the higher the probability the calculated result is erroneous by a large residual. We show that in the drug-like molecular weight region, HFE predictions can easily be off by 5 kcal/mol or more. This is likely to be highly problematic in a drug discovery and development setting. These findings should be taken into consideration during development and testing of the next generation of force fields, if they are to usher in the next generation of antineoplastics.


hydration free energy
molecular dynamics
thermodynamic integration
machine learning


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