Exploring Ligand Stability in Protein Crystal Structures Using Binding Pose Metadynamics

Identification of
correct protein–ligand binding poses is
important in structure-based drug design and crucial for the evaluation
of protein–ligand binding affinity. Protein–ligand coordinates are commonly obtained from
crystallography experiments that provide a static model of an ensemble
of conformations. Binding pose metadynamics (BPMD) is an enhanced
sampling method that allows for an efficient assessment of ligand
stability in solution. Ligand poses that are unstable under the bias
of the metadynamics simulation are expected to be infrequently occupied
in the energy landscape, thus making minimal contributions to the
binding affinity. Here, the robustness of the method is studied using
crystal structures with ligands known to be incorrectly modeled, as
well as 63 structurally diverse crystal structures with ligand fit
to electron density from the Twilight database. Results show that
BPMD can successfully differentiate compounds whose binding pose is
not supported by the electron density from those with well-defined
electron density.