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Key Findings and Value at a Glance Understanding how intrinsically disordered proteins interact with biological membranes is a long-standing challenge in biophysics. In a recent study published in Biophysical Chemistry (2026, 329:107550), Dr. Yann Fichou and his team at the University of Bordeaux, France, developed a robust quantitative EPR spectroscopy method to directly measure Tau protein–lipid interactions. Their approach does not rely on indirect probes or relative fluorescence signals, enabling precise, absolute quantification of both free and membrane-bound protein populations. Using the CIQTEK EPR200M benchtop X-band EPR spectrometer, the team quantitatively resolved the binding behavior of Tau protein to negatively charged lipid membranes, extracted absolute concentrations of free and bound protein populations, and determined binding affinity with minimal experimental input. This work not only reveals key mechanistic insights into Tau–membrane interactions, but also demonstrates the power of CW EPR for quantitative analysis in complex biological systems.     Background: Why Quantifying Protein–Lipid Interactions Is So Difficult Protein–lipid interactions play a central role in cellular signaling, membrane organization, and the aggregation of pathological proteins. In neurodegenerative diseases such as Alzheimer’s disease, the interaction between Tau protein and cellular membranes is believed to be a critical early event that triggers pathological aggregation. Despite its importance, quantitative characterization of these interactions remains challenging. Biological membranes are heterogeneous, dynamic, and highly sensitive to experimental conditions. The interactions themselves are often weak, transient, and involve multiple conformational states. Conventional methods such as fluorescence or colorimetric assays typically provide relative signals and require calibration curves that introduce additional uncertainty. EPR spectroscopy offers a fundamentally different approach. By directly probing the dynamics of spin-labeled molecules, quantitative EPR provides a sensitive and accurate window into molecular motion, binding, and conformational restriction, enabling precise determination of protein–lipid interactions.   From Spectral Line Shapes to Molecular Binding Dynamics Tau is an intrinsically disordered protein, and its interaction with lipid membranes involves subtle changes in molecular mobility rather than large structural rearrangements. This makes CW EPR particularly well suited to the problem. Tau protein was site-specifically labeled using site-directed spin labeling (SDSL). Continuous-wave EPR spectra were acquired on the CIQTEK EPR200M at room temperature and 150 K while increasing the concentration of POPS multilamellar vesicles (MLVs). Free Tau shows a narrow, symmetric three-line spectrum corresponding to rapid isotropic motion (τc ≈ 0.383 ns), characteristic of int...