Absolute Binding Free Energy (ABFE) calculations for bivalent molecular glue ternary systems from [1]. All A3FE input files and the results of 1 ns non-adaptive simulations for 5 replicas are included in their respective folders. The input files include parameterized bound and free systems in .prm7 and .rst7 formats. Original structural files and parameterization scripts are available in the input_prep folder.
For the IBG1–BRD4–DCAF16 and IBG1–BRD3–DCAF16 systems, both Boresch Restraints (BR) and Multiple Distance Restraints (MDR) were tested. For the IBG3–BRD4–DCAF16 system, only MDR was applied. MDR restraints were generated using BioSimSpace, as demonstrated in the restraint_gen.ipynb notebooks. Release free energies were calculated using the mdr-release method described at:
https://github.com/michellab/Multiple-Distance-Restraints
Example input files for each MDR calculation can be found in the get_restraints/release1 folder.
This folder contains the HADDOCK 2.4 webserver input files and the top docking results for the IBG3–BRD4–DCAF16 system. The IBG3_docking_best folder includes 400 water-refined structures, along with the 10 best-ranked structures based on DockQ scores.
The distance restraints used for docking are provided in the IBG3_distance_restraints.tbl file, where:
- BRD4 is segment A
- IBG3 is segment B
- DCAF16 is segment C
The active residues were selected based on references [1] and [2].
[1] Hsia, O., Hinterndorfer, M., Cowan, A.D. et al. Targeted protein degradation via intramolecular bivalent glues. Nature 627, 204–211 (2024). https://doi.org/10.1038/s41586-024-07089-6
[2] Filippakopoulos, P., Qi, J., Picaud, S. et al. Selective inhibition of BET bromodomains. Nature 468, 1067–1073 (2010). https://doi.org/10.1038/nature09504