Umbrella-sampling free energies rank molecular glue ternary complexes
- Molecular dynamics with umbrella sampling, run along a geometric thermodynamic cycle using conformational and orientational restraints, estimates how stable a glue-induced target–E3 ligase complex is.
- Tested on CK1α–lenalidomide–CRBN interface mutants and on BRD4 degraders recruiting DCAF16.
- Results tracked experimental affinities and biophysical trends, and explained BRD4 selectivity via one interfacial glycine, which MM/GBSA and HADDOCK scoring missed.
💡 Points Based on the abstract
Two E3 systems and a handful of mutants is a thin base for calling a protocol predictive, so I'd want a blind, prospective ranking on a chemotype it hasn't seen. Umbrella sampling per complex is also far costlier than MM/GBSA, and glue cooperativity depends on ternary-induced protein-protein contacts. On our own glue series, I'd first test whether it reproduces known SAR cliffs before spending GPU time.
📄 Paper · Journal of Chemical Theory and Computation (ACS) ↗ Predicting Ternary Complex Stability through Binding Free-Energy Calculations in the Geometric Route