Direct Generation of Protein Conformational Ensembles via Machine Learning

ABSTRACT Dynamics and conformational sampling are essential for linking protein structure to biological function. While challenging to probe experimentally, computer simulations are widely used to describe protein dynamics, but at significant computational costs that continue to limit the systems that can be studied. Here, we demonstrate that machine learning can be trained with simulation data to directly generate physically realistic conformational ensembles of proteins without the need for any sampling and at negligible computational cost. As a proof-of-principle a generative adversarial network based on a transformer architecture with self-attention was trained on coarse-grained simulations of intrinsically disordered peptides. The resulting model, idpGAN, can predict sequence-dependent ensembles for any sequence demonstrating that transferability can be achieved beyond the limited training data. idpGAN was also retrained on atomistic simulation data to show that the approach can be extended in principle to higher-resolution conformational ensemble generation.