Long-Range Correlated Dynamics in Intrinsically Disordered Proteins

Abstract

Intrinsically disordered proteins (IDPs) are involved in a wide variety of physiological and pathological processes and are best described by ensembles of rapidly interconverting conformers. Using fast field cycling relaxation measurements we here show that the IDP α-synuclein as well as a variety of other IDPs undergoes slow reorientations at time scales comparable to folded proteins. The slow motions are not perturbed by mutations in α-synuclein, which are related to genetic forms of Parkinson's disease, and do not depend on secondary and tertiary structural propensities. Ensemble-based hydrodynamic calculations suggest that the time scale of the underlying correlated motion is largely determined by hydrodynamic coupling between locally rigid segments. Our study indicates that long-range correlated dynamics are an intrinsic property of IDPs and offers a general physical mechanism of correlated motions in highly flexible biomolecular systems.

Comprehensive structural and dynamical view of an unfolded protein from the combination of single-molecule FRET, NMR, and SAXS

“…Rotational diffusion of the polypeptide chain makes dynamics unobservable via dipolar, chemical shift anisotropy, or quadrupolar relaxation on timescales longer than the rotational time (69). Recently, Parigi et al (70) have shown by 1 H T 1 relaxation dispersion that a number of IDPs exhibit long-range rotational correlation times in the one-digit nanosecond range, which are comparable to folded proteins of similar size. For urea-denatured ubiquitin, 15 N relaxation data (71) indicate an isotropic reorientation of the N-H vectors, which is considerably faster than the rotational correlation time of 4 ns for folded ubiquitin (72).…”

Lokale und globale Dynamik im ungeordneten Synuklein‐Protein

“…as it was done for the experimental data [3] (the fit was in all cases very good, with a reduced χ 2 of about 10…”

“…The first 2-µs of the H-H ACFs were taken for Fourier transformation, as a result, spectral densities from 0 to 50 GHz at 0.5 MHz intervals were obtained. R 1 of all non-exchangeable CH 3 , CH 2 and CH α protons were then calculated from the spectral densities, J(ω), through the equation , (eq. S3)…”

“…The calculations were repeated for proton Larmor frequencies of 0.1, 0.5, 1, 2, 3, 5, 10, 15, 20 30 and 50, corresponding to the range of available experimental data [3] . For R 1 calculation at ω=0.1 MHz, J(0.1MHz) and J(0.2MHz) were approximated by J(0).…”

“…The temperature was set to 25 °C. The pH and temperature were identical to those used for experimental proton relaxometry experiments [3] . 15 N R 1 rates were measured using conventional pulse sequence schemes with ten relaxation delays between 10 and 1000 ms [7] .…”