Identifying Sequence Effects on Chain Dimensions of Disordered Proteins by Integrating Experiments and Simulations

Area of Science:

• Biochemistry
• Structural Biology
• Computational Biology

Background:

• Intrinsically disordered proteins (IDPs) lack stable 3D structures.
• Their conformations are crucial for function and depend on amino acid sequence.
• Understanding sequence-ensemble relationships is key for IDP research.

Purpose of the Study:

• To systematically investigate how amino acid composition dictates the conformational ensembles of intrinsically disordered protein regions.
• To develop a predictive model for disordered protein behavior based on sequence features.

Main Methods:

• Single-molecule Förster resonance energy transfer (smFRET) spectroscopy.
• Circular dichroism (CD), nuclear magnetic resonance (NMR), and small-angle X-ray scattering (SAXS).
• Atomistic simulations with ensemble reweighting and coarse-grained model parametrization.

Main Results:

• Disordered protein chain dimensions varied up to sixfold based on amino acid composition.
• Specific residue types (charged, aromatic, polar) significantly influence intrachain interactions.
• A transferable coarse-grained model accurately described experimental FRET data.

Conclusions:

• Protein sequence composition is a primary determinant of conformational ensembles in intrinsically disordered regions.
• Integrating experimental and simulation approaches provides quantitative insights into IDP behavior.
• The developed model advances the understanding and prediction of disordered protein structures.