Abstract
Intrinsically disordered proteins (IDPs) are essential components for the formation of membraneless organelles, which play key functional and regulatory roles within biological systems. These complex assemblies form and dissolve spontaneously over time via liquid-liquid phase separation of IDPs. Mutations in their amino acid sequence can alter their phase behavior, which has been linked to the emergence of severe diseases such as cancer and neurodegenerative diseases including amyotrophic lateral sclerosis. In this work, we study the conformation and phase behavior of a low-complexity domain of heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1), using coarse-grained implicit solvent molecular dynamics simulations. We systematically analyze how these properties are affected by the number of aromatic residues within the examined sequences. We find a significant compaction of the chains and an increase in the critical temperature with increasing number of aromatic residues within the IDPs. Both observations strongly support the hypothesis that aromatic residues play a dominant role for condensation, which is further corroborated by a detailed analysis of the intermolecular contacts. Interestingly, we observe density inhomogeneities within the condensates near criticality, which are driven by electrostatic interactions. Comparing single-chain and condensed state simulations, we find distinct differences in the conformations of individual chains. By establishing quantitative comparisons to the experimental phase behavior, we start to critically assess the reliability of coarse-grained IDP models.
Competing Interest Statement
The authors have declared no competing interest.
