Repulsive interactions in regulating biomolecular condensation: A case study on TDP-43 and Hero11.

Abstract

Biomolecular condensation is involved in various cellular processes, both functional and dysfunctional. Regulation of the condensation to avoid pathogenetic aggregation is thus crucial to maintaining a stable cellular environment. Using multiscale molecular dynamics simulations, we investigate the role of electrostatic repulsion in the regulation of condensate formed by TDP-43, an aggregation-prone protein, by Hero11, a highly-charged heat-resistant protein. Our results reveal that the solubility of Hero11 is dominated by the repulsive electrostatic interactions coming from its high content of charged residues. By simulating the heterotypic condensation of TDP-43 and Hero11 mixture, we find that Hero11's regulatory effect on TDP-43's phase transition can be explained by a combination of attractive Hero11-TDP-43 interactions and the repulsive Hero11-Hero11 interactions. These interactions increase TDP-43's inter-molecular interactions in the dilute phase, and reduce TDP-43's contact number in the dense phase, which shifts the balance of TDP-43 phase transition. Hero11 also loosens the condensate and facilitates a faster diffusion of TDP-43 in the concentrated phase. Moreover, by employing different modeling of Hero11 with or without alpha-helices, we uncover a secondary structure-dependent positional distribution of client proteins in condensates, where less-helical structures tend to assemble on the surface of the condensates, which can avert droplet fusion. Our results provide new insights into the mechanism of the regulation of biomolecular condensations.