As of 2014, the Protein Data Bank (PDB) has witnessed deposition of 100,000th structure and is growing rapidly with the advent of high throughout crystallography and structural consortium initiatives. X-ray crystal structures containing at least one of >17,000 organic ligand molecules account for 25% of PDB. Current structure refinement and validation protocols are well suited for biomolecular structures like proteins and nucleic acids, but are far from optimal for non-covalently bound ligands in such structures. The undetected errors and uncertainty in the ligand:protein structures can lead to the misinterpretation of experimental data and possible failure of drug discovery efforts.
I will present case studies on the applications of molecular dynamics simulations and free energy calculations in conjunction with well-validated ligand force field parameters in validating and correcting the structure and binding pose(s) of ligands in X-ray crystal structures.