Arginine: I. Interactions of Its Guanidinium Moiety with Branched Aliphatic Side Chains.

The guanidine moiety of arginine side chains in proteins is often close to branched aliphatic side chains. We used the dispersion-corrected ωB97X-D density functional to calculate the interaction energy between the models of Arg and Leu side chains. We found that, in the lowest energy planar-like structures, the amino groups of methylguanidinium ion─our model of Arg side chains, and the methyl groups of 2-methylbutane─our model of leucine or isoleucine side chains, approach each other very closely. In these pairs, the methyl groups of Leu act as bases, donating electrons to the Arg side chains. The shortest distance between hydrogen atoms on different monomers is smaller than the sum of their van der Waals radii (2.2-2.4 Å). The shortest distance between a nitrogen atom of Arg and a carbon atom of Leu in these structures is around 3.4 Å. The stacked-like structures have a higher energy. The charge transfer in these pairs is an order of magnitude smaller. We inspected high-resolution files from the protein data bank (PDB), selected from the PISCES database, and found even closer approaches between Arg and Leu side chains in crystals. Stronger interactions between the side-chain models can be obtained by the second protonation of the guanidinium moiety of Arg. In our calculations for the doubly protonated dimer, the N···C distance decreases to about 3.1 Å, and the H···H distance becomes significantly lower than 2 Å. Our calculations, as well as the inspection of the PDB structures, pose the question of why Leu and Arg side chains approach each other so closely. Can Leu stabilize the doubly protonated guanidinium moiety of Arg, or does an exchange of protons occur between amino and methyl groups, as it does in dihydrogen-bonded complexes? Further experimental studies are needed to answer these questions.