Atomic resolution ensembles of intrinsically disordered and multi-domain proteins with Alphafold

Abstract

Intrinsically disordered proteins are ubiquitous in biological systems and play essential roles in a wide range of biological processes and diseases. Despite recent advances in high-resolution structural biology techniques and breakthroughs in deep learning-based protein structure prediction, accurately determining structural ensembles of IDPs at atomic resolution remains a major challenge. Here we introduce bAIes, a Bayesian framework that integrates AlphaFold2 predictions with physico-chemical molecular mechanics force fields to generate accurate atomic-resolution ensembles of IDPs. We show that bAIes produces structural ensembles that match a wide range of high- and low-resolution experimental data across diverse systems, achieving accuracy comparable to atomistic molecular dynamics simulations but at a fraction of their computational cost. Furthermore, bAIes outperforms state-of-the-art IDP models based on coarse-grained potentials as well as deep-learning approaches. Our findings pave the way for integrating structural information from modern deep-learning approaches with molecular simulations, advancing ensemble-based understanding of disordered proteins.