Submillisecond Atomistic Molecular Dynamics Simulations Reveal Hydrogen Bond-Driven Diffusion of a Guest Peptide in Protein–RNA Condensate

• Published in: The journal of physical chemistry. B 2024-03, Vol.128 (10), p.2347-2359
• Main Authors: Unarta, Ilona C., Cao, Siqin, Goonetilleke, Eshani C., Niu, Jiani, Gellman, Samuel H., Huang, Xuhui
• Format: Article
• Language: English
• Subjects: Arginine - chemistry; B: Biophysical and Biochemical Systems and Processes; Cations; Hydrogen Bonding; Lysine - chemistry; Molecular Dynamics Simulation; Peptides - chemistry; Proteins; RNA
• ISSN: 1520-6106; 1520-5207
• DOI: 10.1021/acs.jpcb.3c08126

Liquid–liquid phase separation mediated by proteins and/or nucleic acids is believed to underlie the formation of many distinct condensed phases, or membraneless organelles, within living cells. These condensates have been proposed to orchestrate a variety of important processes. Despite recent advances, the interactions that regulate the dynamics of molecules within a condensate remain poorly understood. We performed accumulated 564.7 μs all-atom molecular dynamics (MD) simulations (system size ∼200k atoms) of model condensates formed by a scaffold RNA oligomer and a scaffold peptide rich in arginine (Arg). These model condensates contained one of three possible guest peptides: the scaffold peptide itself or a variant in which six Arg residues were replaced by lysine (Lys) or asymmetric dimethyl arginine (ADMA). We found that the Arg-rich peptide can form the largest number of hydrogen bonds and bind the strongest to the scaffold RNA in the condensate, relative to the Lys- and ADMA-rich peptides. Our MD simulations also showed that the Arg-rich peptide diffused more slowly in the condensate relative to the other two guest peptides, which is consistent with a recent fluorescence microscopy study. There was no significant increase in the number of cation–π interactions between the Arg-rich peptide and the scaffold RNA compared to the Lys-rich and ADMA-rich peptides. Our results indicate that hydrogen bonds between the peptides and the RNA backbone, rather than cation–π interactions, play a major role in regulating peptide diffusion in the condensate.