Map conformational landscapes of intrinsically disordered proteins with polymer physics quantities

Area of Science:

• Biophysics
• Structural Biology
• Computational Biology

Background:

• Disordered proteins lack stable structures and sample diverse conformations.
• These proteins are implicated in diseases like Alzheimer's and cancer.
• Understanding their conformational flexibility is key to their function and malfunction.

Purpose of the Study:

• To develop a method for mapping the conformational landscapes of disordered proteins.
• To assess the conformational diversity of disordered proteins and related polymers.
• To utilize polymer physics principles to analyze protein structures.

Main Methods:

• Computed the instantaneous shape ratio (Rs = Ree²/Rg²) and radius of gyration (Rg) for disordered proteins and polymer models.
• Used scatter plots of Rs vs. Rg to visualize conformational landscapes.
• Defined a reference map using Gaussian Walk (GW) polymer models.
• Calculated the fraction of GW conformations (fC) covered by each protein/polymer to assess diversity.

Main Results:

• Disordered proteins exhibit high fC scores, indicating broad conformational sampling.
• Each disordered protein occupies a unique region on the Rs-Rg map, highlighting distinct conformational ensembles.
• Polyethyleneimine (PEI) at various protonation states showed disordered protein-like behavior, with decreasing conformational diversity upon increased protonation.

Conclusions:

• The Rs-Rg scatter plot provides a simple and meaningful map of disordered protein conformational landscapes.
• This method effectively assesses and differentiates the conformational diversity of disordered proteins.
• The approach is applicable to other flexible polymers, such as gene delivery vectors like PEI.