Binding Free Energies without Alchemy
Fuente:
arXiv
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| Autori principali: | , , , , |
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| Natura: | Preprint |
| Pubblicazione: |
2026
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| _version_ | 1866912970545561600 |
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| author | Brocidiacono, Michael Novy, Brandon Dey, Rishabh Popov, Konstantin I. Tropsha, Alexander |
| author_facet | Brocidiacono, Michael Novy, Brandon Dey, Rishabh Popov, Konstantin I. Tropsha, Alexander |
| contents | Absolute Binding Free Energy (ABFE) methods are among the most accurate computational techniques for predicting protein-ligand binding affinities, but their utility is limited by the need for many simulations of alchemically modified intermediate states. We propose Direct Binding Free Energy (DBFE), an end-state ABFE method in implicit solvent that requires no alchemical intermediates. DBFE outperforms OBC2 double decoupling on a host-guest benchmark and performs comparably to OBC2 MM/GBSA on a protein-ligand benchmark. Since receptor and ligand simulations can be precomputed and amortized across compounds, DBFE requires only one complex simulation per ligand compared to the many lambda windows needed for double decoupling, making it a promising candidate for virtual screening workflows. We publicly release the code for this method at https://github.com/molecularmodelinglab/dbfe. |
| format | Preprint |
| id |
arxiv_https___arxiv_org_abs_2603_12253 |
| institution | arXiv |
| publishDate | 2026 |
| record_format | arxiv |
| spellingShingle | Binding Free Energies without Alchemy Brocidiacono, Michael Novy, Brandon Dey, Rishabh Popov, Konstantin I. Tropsha, Alexander Quantitative Methods Absolute Binding Free Energy (ABFE) methods are among the most accurate computational techniques for predicting protein-ligand binding affinities, but their utility is limited by the need for many simulations of alchemically modified intermediate states. We propose Direct Binding Free Energy (DBFE), an end-state ABFE method in implicit solvent that requires no alchemical intermediates. DBFE outperforms OBC2 double decoupling on a host-guest benchmark and performs comparably to OBC2 MM/GBSA on a protein-ligand benchmark. Since receptor and ligand simulations can be precomputed and amortized across compounds, DBFE requires only one complex simulation per ligand compared to the many lambda windows needed for double decoupling, making it a promising candidate for virtual screening workflows. We publicly release the code for this method at https://github.com/molecularmodelinglab/dbfe. |
| title | Binding Free Energies without Alchemy |
| topic | Quantitative Methods |
| url | https://arxiv.org/abs/2603.12253 |