The traditional structure-function paradigm has provided significant insights for well-folded proteins in which structures can be easily and rapidly revealed by X-ray crystallography beamlines and NMR. However approximately one third of the human proteome are comprised of intrinsically disordered proteins and regions that do not adopt a dominant well-folded structure, and therefore remain “unseen” by traditional structural biology methods. Current experimental and computational approaches to structural descriptions of disordered proteins, while often valuable, still lack predictive power, particularly for dynamic complexes of IDPs, as well as lack of insight into the relationships between IDP structural ensembles and function. We made significant progress in the last grant cycle in the following four directions: (1) Generating and quantifying the utility of experimental data types for IDP monomer ensembles; (2) Applying atomistic and coarse-grained physical models and machine learned sampling methods for generating monomer ensembles; (3) Advancing new Bayesian models for IDP monomer ensemble selection; (4) development of highly novel machine learning (ML) methodology for ensemble generation and selection; (5) Creating software and monomer ensemble data and placing them in the hands of practitioners. Many of these results serve as preliminary studies for this renewal and are described in more detail in proposed research. But to fully address the biological activity of IDPs we propose to adapt these computational methods further and develop new integrative biology tools that will be more selective for dynamic associations of IDPs within both discrete dynamic complexes and biological condensates and for post-translational modifications (PTMs) that create relevant IDP functional states. Building on strong preliminary data from our experimental collaborators, we will record NMR, SAXS and single molecule fluorescence data on phosphorylated and non-phosphorylated 4E-binding protein 2 (np-4E-BP2, 5p-4E-BP2) and its dynamic complex with the eukaryotic translation initiation factor (eIF4E); tropoelastin and mixed and condensed-phase elastin fragments; and mixed and condensed-phase CAPRIN1 C-terminal IDR, including novel NMR experiments that probe electrostatic potentials (ESPs), 3-color smFRET, and fluorescence correlation spectroscopy (FCS). These studies will illuminate mechanisms of translational regulation and elasticity, and provide insights into pathological states, including autism spectrum disorder and cardiovascular disease.