Enhanced-sampling simulations uncover hidden surface pockets on the disordered MYC oncoprotein
- MYC, a largely disordered cancer driver long considered undruggable, was probed by combining conventional all-atom molecular dynamics with well-tempered metadynamics on a MYC motif in explicit salt water.
- Representative conformations from the sampled landscape displayed stable, ligand-accommodating pockets, and a known MYC inhibitor docked consistently with electrostatic features.
- Placed in several newly identified pockets, the inhibitor remained bound in long unbiased runs; support is purely computational, with no experimental test.
💡 Points Based on the abstract
A pocket that stays occupied in unbiased MD is weak evidence, since the ligand was placed there and a force field rarely ejects it. The real test is whether those states are populated: metadynamics free energies depend heavily on the collective variables and a disordered motif, and the force field matters a great deal for IDPs. I'd want NMR or SPR with mutants first.
📄 Paper · Journal of Chemical Information and Modeling (ACS) ↗ Drugging Pockets at the Surface of c-MYC Oncoproteins Revealed by Well-Tempered Metadynamics