Below you see arginine. No one (in a million years) would suspect arginine to be a hydrophobic amino acid. This label would go against intuition that comes naturally to a chemist. Yet, hydrophobicity is also context-dependent. As a matter of fact, arginine is a residue par excellence in terms of stacking with aromatic groups, thereby plugging all sorts of hydrophobic pockets. Here is a view from a crystal structure Elena and I solved recently. You see how arginine’s guanidine group is perfectly positioned inside one of the aromatic cages that makes this particular protein special. We want to interrogate the pocket, yet it is filled. Arginine – please go away, darn it! We need our fragments there, not you…