Multi-scale molecular simulation of random peptide phase separation and its extended-to-compact structure transition driven by hydrophobic interactions

Intrinsically disordered proteins (IDPs) often undergo liquid-liquid phase separation (LLPS) and form membraneless organelles or protein condensates. One of the core problems is how do electrostatic repulsion and hydrophobic interactions in peptides regulate the phase separation process? To answer this question, this study uses random peptides composed of positively charged arginine (Arg, R) and hydrophobic isoleucine (Ile, I) as the model systems, and conduct large-scale simulations using all atom and coarse-grained model multi-scale simulation methods. In this article, we investigate the phase separation of different sequences using a coarse-grained model. It is found that the stronger the electrostatic repulsion in the system, the more extended the single-chain structure, and the more likely the system forms a low-density homogeneous phase. In contrast, the stronger the hydrophobic effect of the system, the more compact the single-chain structure, the easier phase separation, and the higher the critical temperature of phase separation. Overall, by taking the random polypeptides composed of two types of amino acid residues as model systems, this study discusses the relationship between the protein sequence and phase behaviour, and provides theoretical insights into the interactions within or between proteins. It is expected to provide essential physical information for the sequence design of functional IDPs, as well as data to support the diagnosis and treatment of the LLPS-associated diseases. Stronger hydrophobic interactions result in more compact single-chain structures, elevating the tendency as well as the critical temperature of phase separation.

Automated summary

This study investigates the regulation mechanisms of electrostatic repulsion and hydrophobic interactions in the phase separation of proteins. The results reveal that stronger electrostatic repulsion leads to more extended single-chain structures and a higher probability of low-density homogeneous phase formation. On the other hand, stronger hydrophobic effect results in more compact single-chain structures, facilitating phase separation and increasing the critical temperature.