Although they populate diverse conformational ensembles, intrinsically disordered proteins have well-defined functions determined by their equilibrium and dynamic properties. Such properties can be probed by single-molecule FRET experiments, which have revealed a strong dependence of the equilibrium degree of compaction on sequence for a set of 16 naturally occurring disordered regions of the same length from RNA-binding proteins. Remarkably, however, we find chain reconfiguration times measured for the same proteins to be almost independent of sequence, although chain dynamics would be expected to be slower for more compact proteins because of stronger intrachain interactions leading to increased internal friction. We investigate this effect with the aid of multi-microsecond, all-atom explicit-solvent simulations of all 16 disordered proteins. The simulations reproduce the experimental FRET efficiencies across the sequence set with near-quantitative accuracy. Explicitly including the FRET dyes improves agreement while minimally perturbing the protein ensemble, with residual deviations arising mainly from slightly overstabilized salt bridges. The simulations further reproduce the experimentally observed lack of correlation between reconfiguration times and chain dimensions across sequences. We are able to rationalize this observation as arising from two compensating factors as the chains get more compact: The narrowing of end-to-end equilibrium distance distributions and a concomitant reduction of the effective end-to-end diffusion coefficients have opposite effects that result in the the small variation of reconfiguration times with protein collapse, helping to "buffer" the effect of sequence on linker dynamics.
Ivanović et al. (2025) studied this question.