Abstract
Protein-protein interfaces are often stabilized by a small number of dominant contacts, exemplified by the overrepresentation of arginine residues at oligomerization interfaces. Positively charged arginines are most commonly involved in ion pairs of opposite charge; however, previous work of Scheraga and co-workers described the stable, close range interaction between guanidinium pairs in a solvated environment. To extend this work, we searched over 70 thousand protein structures and complexes for unusual formations of arginine residues supported by the electron density. Symmetry transformations were used to generate full assemblies. Clusters of four to eight arginine residues with C(ζ)-C(ζ) distances <5 Å, organized as rings with four to eight members, stacks of two arginines, and strings of stacked arginines, are commonly located at the interfaces of oligomeric proteins. The positive charge is properly balanced by negatively charged counterions in about 90% of the cases. We also observed planar stacking of guanidinium groups, bridged by hydrogen bonds and interactions with water molecules. The guanidinium groups are commonly involved in five hydrogen bonds with water molecules and acceptor groups from surrounding amino acids. Water molecules have a bridging effect on the arginine pairs, but in some cases, small molecular weight chemicals in the crystallization buffer may be misinterpreted as water molecules. In summary, despite electrostatic repulsion, arginines do form various clusters that are exposed to interact with and potentially be controlled or switched by charged metabolites, membrane lipids, nucleic acids, or side chains of other proteins. Control of the stability of arginine clusters may play an important role in protein-protein oligomerization, molecular recognition, and ligand binding.