doi:10.1093/bioinformatics/btaf499engGarcía-Cebollada, HelenaLópez, AlfonsoAngarica, Vladimir E.Galano-Frutos, Juan JoséSancho, JavierProteinLIPs: a web server for identifying highly polar and poorly packed interfaces in proteinsART-2025-145802Motivation The stability of protein interfaces influences protein dynamics and unfolding cooperativity. Although in some cases the dynamics of proteins can be deduced from their topology, much of the stability of an interface is related to the complementarity of the interacting parts. It is also important to note that proteins that display non-cooperative unfolding cannot be rationally stabilized unless the regions that unfold first are known. Being able to identify protein interfaces that are significantly less stable would contribute to our understanding of protein dynamics and be very valuable in guiding the rational stabilization of proteins with non-two-state unfolding equilibria. Results We introduce ProteinLIPs, a web server that detects interfaces of high polarity and low packing density, termed LIPs. Each LIP consist of a continuous sequence segment (mLIP) plus its contacting residues (cLIP). ProteinLIPs scans monomeric and oligomeric proteins and provides graphical sequence profiles and interactive 3D visualizations of the detected LIPs. Statistical analysis of 53 protein domains from 10 superfamilies shows the two parts of a LIP present distinct characteristics. mLIPs are conserved, structurally unstable and enriched in polar residues, whereas cLIPs are more stable, less conserved, and enriched in apolar residues. Besides, cLIPs are enriched in small-molecule binding site residues, suggesting they play a role in ligand interaction, likely facilitated by instability of the associated mLIPs. ProteinLIPs provides a user-friendly platform for the automated identification and visualization of LIPs and can be used to guide the engineering of non-two-state proteins where LIPs constitute preferential targets for thermostabilization.2025http://zaguan.unizar.es/record/16373210.1093/bioinformatics/btaf499http://zaguan.unizar.es/record/163732oai:zaguan.unizar.es:163732info:eu-repo/grantAgreement/ES/DGA/B23-24info:eu-repo/grantAgreement/ES/DGA/E45-23Rinfo:eu-repo/grantAgreement/EC/H2020/101004806/EU/MOlecular-Scale Biophysics Research Infrastructure/MOSBRIThis project has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement No H2020 101004806-MOSBRIinfo:eu-repo/grantAgreement/ES/MICINN/PID2022-141068NB-I00Bioinformatics 41, 9 (2025), 9byhttps://creativecommons.org/licenses/by/4.0/deed.esinfo:eu-repo/semantics/openAccess