The free-energy surfaces that underlie the conformational distributions of intrinsically disordered proteins (IDPs) are shallow and lack the deep minima characteristic of stable, folded structures. However, even in the absence of secondary or tertiary structure, sequence patterning can lead to conformational preferences and changes in chain dimensions as a function of solution conditions. While patterning effects have received extensive attention from simulation and theory, there is little corresponding data from experiment. Here we investigate the impact of charge patterning on chain dimensions and dynamics in a set of specifically designed polyampholytic IDP variants across the natural range of charge segregation with single-molecule FRET, nanosecond fluorescence correlation, circular dichroism, and NMR spectroscopy. We find that the conformational ensembles and their cooperative response to salt concentration show prominent and systematic dependencies on charge patterning, and to some extent on residue type. In contrast, chain dynamics remain in the tens-of-nanosecond range, consistent with the absence of pronounced free-energy barriers. In close combination with molecular simulations, we show how the concept of susceptibility can be used to quantify cooperativity in the absence of barriers and relate it to the shallow free-energy surfaces of IDPs.
von Roten, V., Ivanovic, M. T., Gopi, S. R., Holla, A., Prestel, A., Nüesch, M., Tamburrini, K. C., Nettels, D., Kragelund, B. B., Best, R., Schuler, B.
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