Marker-free protein study by amplified light scattering

Any spectroscopic method based on exciting a sample through resonant or non-resonant interactions with a light source reaches a detection limit when too few photons interact with the sample. With light scattering techniques for instance, samples that are deemed too transparent cannot be measured. Solutions around this problem include means to increase the cross-section of the interactions (absorption, fluorescence, or scattering) using various probes. While such measurements are widely performed and valid most of the time, this approach can be problematic if the marker is large enough to perturb the system or introduces possible artifacts. Meanwhile, such solutions do not break the fundamental limit that the light source most generally travels through - and interact with - the sample only once. Here, we propose a technique called Cavity Amplified Scattering Spectroscopy (CASS) that amplifies weak light scattering signals typically by a factor 10³, and thus allows us to study quasi non-scattering objects with no added probe. We measured the radius of gyration of highly diluted proteins well beyond the limit of current techniques, and the spectrum of internal protein motion was obtained over a 9-decades wide frequency domain. Having no complex sample preparation, and a simple and compact optical setup, CASS represents an attractive complement to other techniques for the study of internal protein dynamics, and can therefore extend the scope of current light scattering techniques.