• RING-PyMOL is a plugin for PyMOL providing a set of analysis tools for structural ensembles and molecular dynamic (MD) simulations. RING-PyMOL combines residue interaction networks, as provided by the RING software, with structural clustering to enhance the analysis and visualization of the conformational complexity. It combines precise calculation of non-covalent interactions with the power of PyMOL to manipulate and visualize protein structures. The plugin identifies and highlights correlating contacts and interaction patterns that can explain structural allostery, active sites and structural heterogeneity connected with molecular function. It is easy to use and extremely fast, processing and rendering hundreds of models and long trajectories in seconds. RING-PyMOL generates a number of interactive plots and output files for use with external tools. The underlying RING software has been improved extensively. It is ten times faster, can process mmCIF files and it identifies typed interactions also for nucleic acids. Availability and implementation https://github.com/BioComputingUP/ring-pymol

The Prolyl Hydroxylases (PHDs) are an enzymatic family that regulates cell oxygen-sensing. PHDs hydroxylate hypoxia-inducible transcription factors α (HIFs-α) driving their proteasomal degradation. Hypoxia inhibits PHDs activity, inducing HIFs-α stabilization and cell adaptation to hypoxia. As a hallmark of cancer, hypoxia promotes neo-angiogenesis and cell proliferation. PHD isoforms are thought to have a variable impact on tumor progression. All isoforms hydroxylate HIF-α (HIF-1,2,3α) with different affinities. However, what determines these differences and how they pair with tumor growth is poorly understood. Here, molecular dynamics simulations were used to characterize the PHD2 binding properties in complexes with HIF-1α and HIF-2α. In parallel, conservation analysis and binding free energy calculations were performed to better understand PHD2 substrate affinity. Our data suggest a direct association between the PHD2 C-terminus and HIF-2α that is not observed in the PHD2/HIF-1α complex. Furthermore, our results indicate that phosphorylation of a PHD2 residue, Thr405, causes a variation in binding energy, despite the fact that this PTM has only a limited structural impact on PHD2/HIFs-α complexes. Collectively, our findings suggest that the PHD2 C-terminus may act as a molecular regulator of PHD’s activity.