A Molecular View of Liquid-Liquid Phase Separation of Disordered Proteins

Demixing of protein solutions is a well-known phenomenon that has gained renewed interest due to its role in forming membraneless organelles, especially in the context of intrinsically disordered proteins (IDPs). The molecular driving forces underlying the dense "protein-rich" phase formation are only beginning to be probed. The amino acid composition and the specific arrangement of these in the sequence are expected to play an important role. We have recently developed a computational framework to elucidate the sequence determinants of protein liquid-liquid phase separation (LLPS) and apply it to many different IDPs of interest using coarse-grained molecular dynamics simulations. We demonstrate the effects of sequence and patterning on phase separation as well as the relationship between single chain compaction and phase separation. We further delve into the molecular driving forces underlying phase separation using atomic-resolution molecular dynamics simulations to highlight the contributions of different interaction modes to association of IDP fragments, to provide a mechanistic understanding of their role in driving LLPS.