The Origins of Arginine "Magic": Guanidinium Like-Charge Ion Pairing and Oligoarginine Aggregation in Water by NMR, Cryoelectron Microscopy, and Molecular Dynamics Simulations

The phenomenon of like-charge pairing of hydrated ions is a physical manifestation of the unique solvation properties of certain ion pairs in water. Water's high dielectric constant and related ion screening capability significantly influence the interaction between like-charged ions, with the possibility to transform it - in some cases - from repulsion to attraction. Guanidinium cations (Gdm+) represent a quintessential example of such like-charge pairing due to their specific geometry and charge distribution. In this work, we present experimental quantification of Gdm+ - Gdm+ contact ion pairing in water utilizing nuclear magnetic resonance (NMR) spectroscopy experiments complemented by molecular dynamics (MD) simulations and density functional theory (DFT) calculations. The observed interaction is very weak - about -0.5 kJ mol-1 - which aligns with theoretical estimation from MD simulations. We also contrast the behavior of Gdm+ with NH4+ cations, which do no exhibit contact ion pairing in water. DFT calculations predict that the NMR chemical shift of Gdm+ dimers is smaller than that of monomers, in agreement with NMR titration curves that display a nonlinear Langmuir-like behavior. Additionally, we conducted cryo-electron microscopy experiments on oligoarginines R9, which (unlike nona-lysines K9) exhibit aggregation in water. This points again to like charge pairing of the guanidinium side chain groups, as corroborated also by molecular dynamics simulations of these peptides in water.