Small lattice-protein with a well-folded native state preferentially forms a disordered condensate

Liquid-Liquid Phase Separation (LLPS) of proteins is a ubiquitous feature within cells, playing critical roles in many biological pathways. While phase separation is commonly observed for intrinsically disordered proteins, predicting whether and when certain natively folded proteins may also undergo LLPS remains an open question. Small folded proteins might be the most susceptible to unfolding and phase separation; however, studies on the existence and possible LLPS of small ordered proteins face multiple experimental challenges. To begin addressing this knowledge gap, we perform simulations of a small lattice protein with a well-folded native state. Employing standard Monte Carlo moves and simple energy functions, we find that multiple copies of this lattice protein preferentially unfold each other, forming a disordered condensate at the same temperature where a single copy typically remains well-folded. Mechanistically, intermolecular interactions outcompete intramolecular ones, such that proteins in the condensate have lower energy than in the compact native state. As the number of lattice proteins in the simulation increases, the intra-protein energy saturates, indicating that proteins in the condensate are only partially unfolded. We propose that the tendency of small ordered proteins to form condensates may limit the biological roles of such proteins, as well as contributing to experimental challenges in their detection.