Conformational Disorder and Dynamics of Proteins Sensed by Raman Optical Activity

[Image: see text] Raman optical activity (ROA) spectra of proteins hold a lot of information about their structure in solution. To create a better understanding of the ROA spectra of, among others, the intrinsically disordered proteins (IDPs), involved in neurodegenerative diseases, the effect of conformational disorder and dynamics on the ROA spectra was studied. Density functional theory (DFT) calculations of small ensembles of model peptides with increasing disorder show that the ROA patterns of α-helical and polyproline II (PPII) structure reflect the average backbone angles in the ensemble. The amide III region in the ROA spectra of the α-helical peptides is shown to retain its typical −/+/+ pattern, while the amide III region of PPII secondary structure diminishes in intensity with increasing structural disorder. The results show that the ROA spectra of IDPs hence more likely stem from short stretches of well-defined PPII helices rather than a very flexible chain. Further DFT calculations support that mixing of PPII with helical secondary structure is consistent with experimental spectra of IDPs, while mixing with β-strand results in spectral patterns that are not observed experimentally. The detailed information obtained from these results contributes to a better understanding of the spectrum–structure relation.