Accurate predictions of disordered protein ensembles with STARLING

Intrinsically disordered proteins and regions (collectively IDRs) are found across all kingdoms of life and have critical roles in virtually every eukaryotic cellular process¹. IDRs exist in a broad ensemble of structurally distinct conformations. This structural plasticity facilitates diverse molecular recognition and function^2-4. Here we combine advances in physics-based force fields with the power of multi-modal generative deep learning to develop STARLING, a framework for rapid generation of accurate IDR ensembles and ensemble-aware representations from sequence. STARLING supports environmental conditioning across ionic strengths and demonstrates proof of concept for the interpolative ability of generative models beyond their training domain. Moreover, we enable ensemble refinement under experimental constraints using a Bayesian maximum-entropy reweighting scheme. Beyond ensemble characterization, STARLING sequence representations can be used in multiple ways. We showcase two examples: first, STARLING lets us perform ensemble-based search for 'biophysical look-alikes'. Second, we demonstrate how these latent representations can be used to accelerate ensemble-first sequence design from weeks or hours per candidate to seconds, enabling library-scale designs. Together, STARLING 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 the accuracy of STARLING 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.