Analysis of cyclohexane, cyclopentane, and benzene conformations in ligands for PDB X-ray structures using the Hill-Reilly approach.

Protein structural data are highly valuable for research, and many significant results have been published on their basis. An important part of protein structures is their ligands. The conformation of rings in ligands is crucial for the ligands' scaffold and shape and, therefore, for interactions with their surroundings and the subsequent biological function. For this reason, we developed a workflow to detect conformations of cyclohexane, cyclopentane, and benzene rings. The workflow can process rings originating from ligands, which are parts of experimental protein structures deposited in the Protein Data Bank and determined by X-ray crystallography. This fully automatic workflow utilises the Hill-Reilly approach to calculate puckering angles that quantitatively describe ring conformation. The reproducibility of the workflow is guaranteed by storing datasets within Onedata, which enables automatic dataset retrieval and the workflow execution. We analysed 128 012 ring structures originating from 25 479 different ligands. We found that cyclohexane ring structures include more than 22 % of unfavourable conformations, cyclopentane ring structures about 5 % and benzene ring structures only 0.01 %. We discovered that energetically unfavourable ring structures can occur in cyclohexane and cyclopentane ligands for proper chemical reasons. Their examination can help us to understand the binding of these ligands, which can be helpful for pharmacology, chemoinformatics, etc. On the other hand, energetically unfavourable ring conformations are often caused by model quality issues. Therefore, their occurrence should motivate researchers to inspect the quality of the protein model and also the ring's fit into experimental data.Scientific Contribution: Our analysis uncovers a conformational behaviour of cyclohexane, cyclopentane, and benzene rings, occurring in ligands, which are parts of experimental protein structures deposited in the PDB. This paper's other substantial contribution is presenting the first successful application of the Hill-Reilly approach for cyclohexane, cyclopentane, and benzene rings. Moreover, we provide Hill-Reilly parameters for these ring conformations, which can be used in other analyses.