Abstract The ability of electron paramagnetic resonance (EPR) spectroscopy to handle heterogeneous samples is particularly valuable to study structure and dynamics of intrinsically disordered proteins/peptides (IDPs). Such proteins lack a well-defined secondary structure. Site-directed spin-labeling (SDSL), which is the introduction of paramagnetic labels, must ensure that the properties of IDPs remain intact. In this work, amyloid beta (Aβ) peptides spin labeled with the non-canonical amino acid PROF and with MTSL bound to cysteine are investigated and compared. Focusing on the structural integrity and aggregation behavior, it is shown that PROF is a suitable spin label for Aβ. Spin labeling with both PROF and MTSL leads to similar characteristic structural details of Aβ peptides, i.e., random coil and β-sheets, as well as similar rotational mobility in solution. The use of the non-canonical amino acid PROF for spin labeling of IDPs can be superior in respect to linker stability, particularly in EPR studies under physiological conditions, and when naturally occurring cysteines are essential for the protein function.
Mause et al. (Sun,) studied this question.
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