Dynamical Buffering of Reconfiguration Dynamics in Intrinsically Disordered Proteins

Area of Science:

• Biophysics
• Protein Dynamics
• Molecular Biology

Background:

• Intrinsically disordered proteins (IDPs) possess dynamic conformational ensembles essential for their function.
• The relationship between the amino acid sequence of IDPs and their chain dynamics is not well understood.
• Understanding IDP dynamics is key to deciphering their roles in cellular processes.

Purpose of the Study:

• To investigate how sequence composition affects the dynamics of intrinsically disordered protein regions.
• To explore the relationship between chain dimensions and reconfiguration times in diverse IDP sequences.
• To elucidate the molecular mechanisms underlying the observed dynamics.

Main Methods:

• Single-molecule Förster Resonance Energy Transfer (smFRET) to infer chain dimensions.
• Nanosecond Fluorescence Correlation Spectroscopy (nsFCS) to measure chain reconfiguration times.
• Multimicrosecond all-atom explicit-solvent molecular dynamics (MD) simulations.

Main Results:

• Chain dimensions varied significantly with sequence, as inferred from smFRET.
• Chain reconfiguration times measured by nsFCS showed minimal dependence on sequence composition.
• MD simulations accurately reproduced experimental FRET efficiencies and confirmed the lack of correlation between reconfiguration times and chain dimensions.

Conclusions:

• Compensating dynamic factors, namely narrowing end-to-end distance distributions and reduced intrachain diffusion, buffer the effect of sequence on linker dynamics.
• This buffering mechanism may allow for functional conservation across evolving IDP sequences.
• The study provides a molecular-level explanation for the sequence-independent dynamics observed in certain disordered protein regions.