Multiscale approaches to model the functions of Ubiquitin and SUMO modifications in protein phase separation

The post-translational modifiers such as mono and poly ubiquitins and SUMOs are known for their ability to modulate protein–protein interactions by becoming covalently attached to other target proteins. Despite the high similarity in the tertiary structure and sequence, they differentially influence the target protein properties. In this work, we employed a multiscale simulation approach that encompasses atomistic to different level coarse-grained modeling techniques with data-driven machine-learning methods, to explore the structural differences and multidimensional energy landscape of ubiquitin and SUMO and their conjugates. We finally study the influence of distinct features of the targets and modifiers on protein phase separation and aggregation, providing molecular-level insight into the corresponding in vitro measurements and instructing further experiments through adjustment of relevant parameters.