Improving Molecular Docking Pose Recovery through Targeted Side-Chain Monte Carlo Sampling of an Apo Structure

Targeted side-chain MCMC sampling from an apo protease structure recovers ligand poses within 2 Å of experimental positions for 74.4% of 859 OpenBind 2A complexes.

• Why it matters: Apo-only docking is hindered by receptor flexibility, where local side-chain motions can change pocket accessibility and ligand fit, reducing pose recovery.
• What they did: The protocol used targeted Markov Chain Monte Carlo with local and larger torsional proposals plus periodic MD relaxation under harmonic backbone restraints, then compared ensembles to apo and restrained or unrestrained MD.
• The result: MCMC improved median minimum ligand heavy-atom RMSD to 1.62 Å (vs 1.96 Å apo and 1.82 Å restrained MD) and showed larger gains when side-chain displacement exceeded pocket backbone displacement.

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