Rare ring conformations in PDB: Facts or wishful thinking?

Abstract

Protein structural data are highly valuable for research, and many significant results have been published on their basis. A key point for their credibility and applicability is their quality. An important facet of protein structure quality is the validation of ligands. Some aspects of ligand quality have already been validated by established quality metrics. However, validation of ring conformation has yet to be comprehensively performed despite rings strongly influencing the formation of the ligands scaffold and shape. Most rings form several conformations that differ in their stability. The most stable ones occur frequently in nature and should, therefore, be found in Protein Data Bank (PDB) structures. In this article, we examined which conformations of rings occur in PDB structures. Our analysis focused on conformations of all cyclopentane, cyclohexane, and benzene rings in the PDB. Specifically, we examined 123 264 rings of 24 763 distinct ligands, which instances occur in 44 022 protein structures. In general, we found that most of the rings (98.32 %) are in energetically favourable conformations. Surprisingly, the existence of most of the energetically unfavourable ring conformations (2 067 samples, 1.68 %) is not supported by experimental data. Only 291 unfavourable ring conformations (0.24 %) are backed by experimental data that are accurate enough to distinguish the conformation, which shows that the existence of energetically unfavourable ring conformations is rarely supported by structural or experimental evidence. Our results suggest that each occurrence of untypical ring conformation in the PDB may indicate a potential error and should be carefully analysed.