Not Only Expansion: Proline Content and Density Also Induce Disordered Protein Conformation Compaction

Area of Science:

• Biochemistry
• Computational Biology
• Structural Biology

Background:

• Intrinsically disordered proteins (IDPs) lack stable structures and adopt diverse conformations.
• Proline residues are common in IDPs and known to influence protein structure.

Purpose of the Study:

• To investigate the impact of proline residue clustering and isolation on the conformational dynamics of IDPs.
• To understand how proline's organizational pattern affects IDP gyration radii and overall structure.

Main Methods:

• High-resolution atomistic molecular dynamics simulations.
• Design of peptide series varying in proline number and organization.
• Bioinformatic analysis of proline distribution in IDPs.
• Implementation in coarse-grained molecular dynamics models.

Main Results:

• Proline arrangement (clustered vs. isolated) significantly impacts IDP gyration radii, more so than total proline content.
• Clustered prolines expand IDP conformations (~20%) via PPII elements.
• Isolated prolines compact IDP conformations (~10%) via backbone turns.
• Proline's dual role offers a rapid conformational switching mechanism.

Conclusions:

• The spatial organization of proline residues is critical for determining IDP conformational states.
• Proline's opposing effects provide a mechanism for rapid conformational switching in IDPs.
• Improved coarse-grained models incorporating proline patterns enhance IDP conformational ensemble characterization.