Sequence charge decoration dictates coil-globule transition in intrinsically disordered proteins

Area of Science:

• Biophysics
• Computational Biology
• Protein Science

Background:

• Intrinsically disordered proteins (IDPs) lack stable 3D structures, complicating their function prediction.
• Understanding IDP conformational changes is crucial for deciphering their biological roles.

Purpose of the Study:

• To develop an analytical theory for computing heteropolymer conformations, applicable to disordered proteins.
• To investigate the influence of temperature and charge sequence on protein coil-globule transitions.
• To explore how sequence modifications and post-translational modifications affect IDP conformations.

Main Methods:

• Analytical theory development for heteropolymer conformation prediction.
• Benchmarking against all-atom Monte Carlo simulations (CAMPARI) for intrinsically disordered proteins.
• Application to predict conformations of all naturally occurring IDPs in the DisProt database.
• Analysis of post-translational modification effects, such as phosphorylation, on IDP size and conformation.

Main Results:

• The theory accurately describes coil-globule transitions and is validated by simulations.
• Minor sequence charge alterations can lead to drastic conformational changes (coil-to-globule and vice versa).
• A significant variation in IDP size exists even among proteins with similar charge compositions.
• Specific phosphorylation sites ('hot spots') can maximally alter IDP conformation.

Conclusions:

• The developed theory provides a framework to predict and control IDP conformations by tuning temperature and charge.
• Insights into sequence-conformation relationships are provided for IDPs in the DisProt database.
• The study highlights the significant impact of post-translational modifications on IDP structure and function, identifying key modification sites.