Addressing the flexibility issue in protein-ligand binding

Please note that this seminar will now be held on 4th July.

Quantitative understanding of molecular recognition is crucial for basic research and for structure-based drug design. Key to this goal is the knowledge of the atomic-level structures of the complexes formed by receptors and their ligands.

Determining the structure of a protein by experimental techniques remains a quite demanding task in terms of both cost and duration of the experiments. Computational methods have become a valid complement to experiments, although inaccuracy increases with the extent of the conformational changes associated to protein-ligand binding.

To address this limitation, we recently introduced “EDES - Ensemble Docking with Enhanced-sampling of pocket Shape” a computational method based on metadynamics simulations to generate holo-like conformations of proteins by only exploiting their apo structure.

Here, we present an improved version of the original protocol enabling to handle multiple - allosteric - binding sites in extremely flexible proteins.

We applied our method to a very challenging target, namely the enzyme adenylate kinase (AK), which undergoes very large conformational changes upon ligand binding. Our protocol generated a significant fraction of structures featuring a low RMSD from the experimental geometry of the complex between AK and an inhibitor. These conformations were used in ensemble docking calculations yielding to native-like poses of substrates and inhibitors of adenylate kinase among the top-ranked ones.