# Dynamical Buffering of Reconfiguration Dynamics in Intrinsically Disordered Proteins

## TL;DR

This paper explores how disordered proteins maintain consistent dynamics despite sequence differences, revealing a buffering mechanism that preserves function.

## Contribution

The study identifies a novel dynamical buffering effect in disordered proteins that decouples reconfiguration times from sequence composition.

## Key findings

- Reconfiguration times of disordered proteins are nearly sequence-independent despite varying chain dimensions.
- Simulations show that narrowing end-to-end distance distributions and reduced diffusion coefficients balance each other.
- This buffering effect may help maintain functional dynamics as protein sequences evolve.

## Abstract

The dynamics of intrinsically disordered proteins are
important
for their function, allowing their heterogeneous conformational ensembles
to rapidly reconfigure in response to binding partners or changes
in solution conditions. However, the relation between sequence composition
and chain dynamics has rarely been studied. Here, we characterize
the dynamics of a set of 16 naturally occurring disordered regions
of identical chain length but with highly diverse sequences. In spite
of the strong variation of chain dimensions with sequence in this
set inferred from single-molecule FRET, nanosecond fluorescence correlation
spectroscopy yields chain reconfiguration times that are almost independent
of sequence. This surprising observation contrasts with the slowdown
in dynamics, attributed to internal friction, that has been observed
in more compact disordered proteins. We investigated this effect with
the aid of multimicrosecond, all-atom explicit-solvent simulations
of all 16 disordered proteins. The simulations reproduce the experimental
FRET efficiencies with near-quantitative accuracy, with explicit inclusion
of the FRET dyes improving agreement with experiment while minimally
perturbing the protein ensemble. Critically, the simulations also
reproduce the lack of correlation between reconfiguration times and
chain dimensions across the sequences and allow us to rationalize
this observation as arising from two competing factors as the chains
get more compact. The narrowing of end-to-end distance distributions
and a concomitant reduction of the corresponding intrachain diffusion
coefficients have opposite effects that end up resulting in only a
small variation of reconfiguration times with chain dimensions. These
compensating factors “buffer” the effect of sequence
on linker dynamics, which may help to conserve function as sequences
evolve.