Accurate predictions of conformational ensembles of disordered proteins with STARLING

Abstract Intrinsically disordered proteins and regions (collectively IDRs) are found across all kingdoms of life and play critical roles in virtually every eukaryotic cellular process. In contrast to folded proteins, IDRs lack a stable 3D structure and are instead described in terms of a conformational ensemble, a collection of energetically accessible interconverting structures. This unique structural plasticity facilitates diverse molecular recognition and function; thus, a convenient way to view IDRs is through their ensembles. Here, we combine advances in physics-based force fields for IDPs with the power of modern multi-scale generative modeling to develop STARLING, an approach for the rapid and accurate prediction of IDR ensembles directly from sequence. STARLING enables ensembles of hundreds of conformers to be generated in seconds and works on GPUs and CPUs. This, in turn, dramatically lowers the barrier to the computational interrogation of IDR function through the lens of emergent biophysical properties complementing bioinformatic protein sequence analysis. We evaluate STARLING’s accuracy against extant experimental data and offer a series of vignettes illustrating how STARLING can enable rapid hypothesis generation for IDR function and aid the interpretation of experimental data.