Lambda-ABF-OPES: Faster Convergence with High Accuracy in Alchemical Free Energy Calculations
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arXiv
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| Main Authors: | , , , , , , , |
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| Format: | Preprint |
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2025
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| _version_ | 1866918012499525632 |
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| author | Ansari, Narjes Jing, Zhifeng Francis Gagelin, Antoine Hédin, Florent Aviat, Félix Hénin, Jérôme Piquemal, Jean-Philip Lagardère, Louis |
| author_facet | Ansari, Narjes Jing, Zhifeng Francis Gagelin, Antoine Hédin, Florent Aviat, Félix Hénin, Jérôme Piquemal, Jean-Philip Lagardère, Louis |
| contents | Predicting the binding affinity between small molecules and target macromolecules while combining both speed and accuracy, is a cornerstone of modern computational drug discovery which is critical for accelerating therapeutic development. Despite recent progresses in molecular dynamics (MD) simulations, such as advanced polarizable force fields and enhanced-sampling techniques, estimating absolute binding free energies (ABFE) remains computationally challenging. To overcome these difficulties, we introduce a highly efficient, hybrid methodology that couples the Lambda-Adaptive Biasing Force (Lambda-ABF) scheme with On-the-fly Probability Enhanced Sampling (OPES). This approach achieves up to a nine-fold improvement in sampling efficiency and computational speed compared to the original Lambda-ABF when used in conjunction with the AMOEBA polarizable force field, yielding converged results at a fraction of the cost of standard techniques. |
| format | Preprint |
| id |
arxiv_https___arxiv_org_abs_2502_17233 |
| institution | arXiv |
| publishDate | 2025 |
| record_format | arxiv |
| spellingShingle | Lambda-ABF-OPES: Faster Convergence with High Accuracy in Alchemical Free Energy Calculations Ansari, Narjes Jing, Zhifeng Francis Gagelin, Antoine Hédin, Florent Aviat, Félix Hénin, Jérôme Piquemal, Jean-Philip Lagardère, Louis Chemical Physics Biomolecules Predicting the binding affinity between small molecules and target macromolecules while combining both speed and accuracy, is a cornerstone of modern computational drug discovery which is critical for accelerating therapeutic development. Despite recent progresses in molecular dynamics (MD) simulations, such as advanced polarizable force fields and enhanced-sampling techniques, estimating absolute binding free energies (ABFE) remains computationally challenging. To overcome these difficulties, we introduce a highly efficient, hybrid methodology that couples the Lambda-Adaptive Biasing Force (Lambda-ABF) scheme with On-the-fly Probability Enhanced Sampling (OPES). This approach achieves up to a nine-fold improvement in sampling efficiency and computational speed compared to the original Lambda-ABF when used in conjunction with the AMOEBA polarizable force field, yielding converged results at a fraction of the cost of standard techniques. |
| title | Lambda-ABF-OPES: Faster Convergence with High Accuracy in Alchemical Free Energy Calculations |
| topic | Chemical Physics Biomolecules |
| url | https://arxiv.org/abs/2502.17233 |