Fundamental Challenges and Outlook in Simulating Liquid–Liquid Phase Separation of Intrinsically Disordered Proteins
Khandekar Jishan Bari, Dube Dheeraj Prakashchand
Abstract
Intrinsically disordered proteins (IDPs) populate an ensemble of dynamic conformations, making their structural characterization by experiments challenging. Many IDPs undergo liquid-liquid phase separation into dense membraneless organelles with myriad cellular functions. Multivalent interactions in low-complexity IDPs promote the formation of these subcellular coacervates. While solution NMR, Förster resonance energy transfer (FRET), and small-angle X-ray scattering (SAXS) studies on IDPs have their own challenges, recent computational methods draw a rational trade-off to characterize the driving forces underlying phase separation. In this Perspective, we critically evaluate the scope of approximation-free field theoretic simulations, well-tempered ensemble methods, enhanced sampling techniques, coarse-grained force fields, and slab simulation approaches to offer an improved understanding of phase separation. A synergy between simulation length scale and model resolution would reduce the existing caveats and enable theories of polymer physics to elucidate finer details of liquid-liquid phase separation (LLPS). These computational advances offer promise for rigorous characterization of the IDP proteome and designing peptides with tunable material and self-assembly properties.