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

Linking the sequences of intrinsically disordered regions (IDRs) to their structural ensembles and biological functions remains a central challenge in understanding how disorder relates to an activity. A recent study has shown that human IDRs with different levels of compactness, as measured by Flory's exponent (ν), are associated with specific cellular functions and locations, and Flory's exponent can be predicted from sequence features with reasonable accuracy. However, IDRs are known to sample highly heterogeneous conformations that can be masked by ensemble-averaged metrics such as ν. Here, we provide a simple framework that resolves heterogeneous conformations. We pair two polymer physics descriptors, shape ratio (R_s) and relative shape anisotropy (RSA), to construct joint two-dimensional (RSA, R_s) maps at both the global and local (subchain) scales. We show two sequences that have similar values of ν but display strikingly different (RSA, R_s) maps, reflecting differences in their respective charge patterns. We also show two IDRs that have similar global maps but exhibit markedly different local maps that can be linked to local sequence variations. Further analysis of global and local properties reveals a class of IDRs that appear noncompact globally but contain locally compact subchains. These locally compact IDRs are found to be associated with similar Gene Ontology (GO) functional and cellular localization enrichments and phase-separation propensities as globally compact IDRs. Our framework moves beyond ensemble-averaged descriptors, providing new tools that capture the intrinsic heterogeneity of IDR conformations, and thus offers new opportunities to link IDR sequences with functions.