Comparative study of protein X-ray and NMR structures: molecular docking-based virtual screening

Abstract Molecular docking-based virtual ligand screening is a powerful computational approach for identifying potential binders from large chemical libraries. Protein structures used in docking screens are commonly derived from X-ray crystallography or NMR spectroscopy, yet their impact on screening performance remains unclear. To address this, we conducted virtual screening using Glide against both apo and holo X-ray and NMR structures of 18 proteins. While no statistically significant difference in screening performance was observed for apo structures overall, X-ray apo structures tended to perform better in cases where better ligand enrichment than random selection was achieved. Similarly, single holo X-ray and NMR structures did not exhibited statistically significant difference in screening performance either. However, when multiple holo X-ray structures and NMR conformers (from one PDB ensemble) per protein were used, X-ray structures outperformed NMR conformers in most cases. In addition, for consensus enrichment which leverages multiple structures/conformers per protein to optimise ligand ranking, X-ray holo structures exhibited better performance than NMR holo conformers, suggesting that X-ray structures with chemically diverse co-crystalized ligands may introduce more relevant binding-site configurations than the NMR conformers with higher structural diversity but the same bound ligand. Overall, the better performance by X-ray holo structures could be partially attributed to the higher numbers of hydrogen bonds and hydrophobic contacts, formed between proteins and docked ligands. Competing Interest Statement The authors have declared no competing interest.