Challenges in studying the liquid-to-solid phase transitions of proteins using computer simulations

Membraneless organelles, also referred to as biomolecular condensates, perform a variety of cellular functions and their dysregulation is implicated in cancer and neurodegeneration. In the last two decades, liquid-liquid phase separation (LLPS) of intrinsically disordered and multidomain proteins has emerged as a plausible mechanism underlying the formation of various biomolecular condensates. Further, the occurrence of liquid-tosolid transitions within liquid-like condensates may give rise to amyloid structures, implying a biophysical link between phase separation and protein aggregation. Despite significant advances, uncovering the microscopic details of liquid-to-solid phase transitions using experiments remains a considerable challenge and presents an exciting opportunity for the development of computational models which provide valuable, complementary insights into the underlying phenomenon. In this review, we first highlight recent biophysical studies which provide new insights into the molecular mechanisms underlying liquid-to-solid (fibril) phase transitions of folded, disordered and multi-domain proteins. Next, we summarize the range of computational models used to study protein aggregation and phase separation. Finally, we discuss recent computational approaches which attempt to capture the underlying physics of liquid-to-solid transitions along with their merits and shortcomings.

Automated summary

Membraneless organelles, or biomolecular condensates, have important cellular functions and their dysfunction is related to cancer and neurodegeneration. Liquid-liquid phase separation is a possible mechanism for the formation of biomolecular condensates. Liquid-like condensates can undergo liquid-to-solid phase transitions, leading to the formation of amyloid structures. Experimental studies on the microscopic details of these transitions present a challenge, but computational models can provide valuable insights. This review highlights recent biophysical studies on the phase transitions of proteins and summarizes the range of computational models used to study protein aggregation and phase separation.