Conformational energy range of ligands in protein crystal structures: The difficult quest for accurate understanding

• Published in: Journal of molecular recognition 2017-08, Vol.30 (8), p.n/a
• Main Authors: Peach, Megan L., Cachau, Raul E., Nicklaus, Marc C.
• Format: Article
• Language: English
• Subjects: Animals; Binding energy; Binding Sites; conformational energy; Constraints; Crystal structure; Crystallography, X-Ray; Docking; Drug Design; Electron density; Electrostatics; Errors; Humans; Ligands; Molecular Docking Simulation; molecular modeling; Pharmacology; Protein Binding; Protein Conformation; Proteins; Proteins - agonists; Proteins - antagonists & inhibitors; Proteins - chemistry; quality metrics; Solubility; Solvation; Static Electricity; structure refinement; Thermodynamics; Weighting; X‐ray crystallography
• ISSN: 0952-3499; 1099-1352; 1099-1352
• DOI: 10.1002/jmr.2618

In this review, we address a fundamental question: What is the range of conformational energies seen in ligands in protein‐ligand crystal structures? This value is important biophysically, for better understanding the protein‐ligand binding process; and practically, for providing a parameter to be used in many computational drug design methods such as docking and pharmacophore searches. We synthesize a selection of previously reported conflicting results from computational studies of this issue and conclude that high ligand conformational energies really are present in some crystal structures. The main source of disagreement between different analyses appears to be due to divergent treatments of electrostatics and solvation. At the same time, however, for many ligands, a high conformational energy is in error, due to either crystal structure inaccuracies or incorrect determination of the reference state. Aside from simple chemistry mistakes, we argue that crystal structure error may mainly be because of the heuristic weighting of ligand stereochemical restraints relative to the fit of the structure to the electron density. This problem cannot be fixed with improvements to electron density fitting or with simple ligand geometry checks, though better metrics are needed for evaluating ligand and binding site chemistry in addition to geometry during structure refinement. The ultimate solution for accurately determining ligand conformational energies lies in ultrahigh‐resolution crystal structures that can be refined without restraints. What is the range of conformational energies seen in ligands in protein‐ligand crystal structures? We synthesize results from previous computational studies of this issue and conclude that high energies are present in some crystal structures, whereas errors are mainly due to the weighting of ligand stereochemical restraints relative to structure fitting into the electron density. The solution for accurately determining ligand conformational energies is ultrahigh‐resolution crystal structures, which can be refined without restraints.