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Arginine



Arginine gives us a positive outlook. There is simply too much negativity in life! Nucleic acids are polyanionic, membrane-forming lipids are in best case zwitter-ionic, but most often negatively charged. Who would be willing to interact with such a problematic company? I’ll tell you: peptides full of arginine.

Arginine is ‘mister positive’ in the protein structures. Well, what’s about lysine? This is positively charged too, but a simple amino-group is more prone to post-translational modifications, and in general lysine is way more susceptible to chemical transformations. Arginine has a positively charged guanidinium ion, and this is a very stable structure. Organic chemists even invented the concept of Y-aromaticity in order to point out its remarkable stability. Guanidinium ion is so stable, that its positive charge can be hardly removed, having pKa around 12.5. Therefore the side chain ensures positive charge of this residue, unless there is metal coordination, which happens also frequently with arginine residues in catalytic centers of enzymes.

In addition to the positive charge stability, the guanidinium structure is also very well fitted for intimate interaction with negatively charged counterparts: phosphates and carboxylates. The stability of resulting salt-bridges is ensured by both electrostatic interactions and hydrogen bonds between the interacting fragments:



Not surprisingly, arginine-rich sequences can fabulously interact with both, nucleic acids and lipid membranes. For instance, membrane-interactine oligoarginine peptides are well-known cell-penetrating sequences, these are often employed for intracellular delivery of various molecular targets. Or another example would be arginine fork, a special motif of arginines interacting with non-double stranded nucleic acids.


Interesting readings:

- Woods, A. S. and Ferré, S. Amazing Stability of the Arginine-Phosphate Electrostatic Interaction. J. Proteome Res., 4, 2005, 1397-1402, doi: 10.1021/pr050077s

A salt-bridge between an arginine and a phospo-serine can be as strong as a covalent bond.

- Futaki, S. Oligoarginine vectors for intracellular delivery: Design and cellular-uptake mechanisms. Pept. Sci., 84, 2006, 241-249, doi: 10.1002/bip.20421

The review illustrates design of cell delivery vectors with oligoarginine sequences.

- Xiang, S. and Tong, L. Crystal structures of human and Staphylococcus aureus pyruvate carboxylase and molecular insights into the carboxyltransfer reaction. Nat. Struct. Mol. Biol., 15, 2008, 295-302, doi: 10.1038/nsmb.1393

There is a cluster of tightly bundeled four arginine residues in this structure. This is responsible for the phosphate binding in coenzyme A.