Resolving Local and Global Conformational Heterogeneity of the Human Intrinsically Disordered Proteome

Area of Science:

• Biophysics
• Structural Biology
• Computational Biology

Background:

• Intrinsically disordered regions (IDRs) link sequence to structural ensembles and biological functions, a key challenge in protein science.
• Existing metrics like Flory's exponent (ν) provide ensemble-averaged compactness but mask conformational heterogeneity in IDRs.
• Understanding IDR conformational heterogeneity is crucial for linking their sequences to specific cellular activities.

Purpose of the Study:

• To develop a framework for resolving heterogeneous conformations of intrinsically disordered regions (IDRs).
• To investigate how polymer physics descriptors can capture nuanced structural properties beyond ensemble-averaged metrics.
• To establish new methods for linking IDR sequences to their diverse biological functions through detailed conformational analysis.

Main Methods:

• Paired two polymer physics descriptors, shape ratio (Rs) and relative shape anisotropy (RSA), to create 2D (RSA, Rs) maps.
• Analyzed global and local (subchain) scales to resolve conformational heterogeneity.
• Correlated structural properties with sequence features, Gene Ontology (GO) functions, and phase-separation propensities.

Main Results:

• Demonstrated that sequences with similar Flory's exponent (ν) can exhibit distinct (RSA, Rs) maps due to differing charge patterns.
• Identified IDRs with similar global maps but different local maps, linked to local sequence variations.
• Discovered a class of IDRs that are globally noncompact but contain locally compact subchains, associated with compact IDR functions.

Conclusions:

• The developed framework effectively resolves conformational heterogeneity in IDRs, moving beyond ensemble-averaged descriptors.
• Local and global conformational properties derived from (RSA, Rs) maps provide deeper insights into IDR sequence-function relationships.
• This approach offers novel tools for understanding the functional implications of protein disorder and sequence variations.