Protein arginine methylation rewires molecular interactions.

Protein arginine methyltransferases (PRMT1-9) catalyze monomethylation and dimethylation of arginine residues in RNA- and DNA-associated proteins. Protein arginine methylation can weaken or strengthen nucleic acid binding, recruit or exclude protein partners, and promote or suppress higher-order assembly, making its molecular consequences highly context dependent. Methylation preserves the cationic character of the guanidinium group, while altering hydrogen-bond donor topology, steric accessibility, and interaction geometry. These effects are particularly consequential in intrinsically disordered regions (IDRs), where arginine-rich motifs mediate multivalent protein-protein and protein-nucleic acid interactions. Here, we propose an interaction-equilibrium framework in which arginine methylation redistributes binding capacity among the competing protein, nucleic acid, and assembly states. This framework integrates reader-dependent and reader-independent effects of methylarginine and provides a chemical basis for understanding how a charge-preserving modification can reweight molecular interactions across diverse cellular contexts.