The Good, the Bad, and the Twisted Revisited: An Analysis of Ligand Geometry in Highly Resolved Protein-Ligand X-ray Structures.

An analysis of the rotatable bond geometry of drug-like ligand models is reported for high-resolution (<1.1 Å) crystallographic protein-ligand complexes. In cases where the ligand fit to the electron density is very good, unusual torsional geometry is rare and, most often, though not exclusively, associated with strong polar, metal, or covalent ligand-protein interactions. It is rarely associated with a torsional strain of greater than 2 kcal mol by calculation. An unusual torsional geometry is more prevalent where the fit to electron density is not perfect. Multiple low-strain conformer bindings were observed in 21% of the set and, it is suggested, may also lie behind many of the 35% of single-occupancy cases, where a poor fit to the e-density was found. It is concluded that multiple conformer ligand binding is an under-recognized phenomenon in structure-based drug design and that there is a need for more robust crystallographic refinement methods to better handle such cases.