The principal driving forces of protein folding are the burial of hydrophobic residues in the interior of proteins and the exposure of charged residues at the surface. Charged residues are only occasionally found in the interior, where they form hydrogen bonds to oppositely charged residues or main-chain atoms. Ribonucleotide reductase, a key enzyme in DNA synthesis, catalyses the de novo production of deoxyribonucleotide precursors. It is composed of two different dimeric proteins R1 and R2 (refs 3-5). R2 subunits contain buried iron-centres with each centre formed by two ferric ions coordinated by four carboxylates and two histidine ligands. Iron-free R2, apoR2, is a precursor of active R2 and folds into a stable protein which is transformed into active R2 by ferrous ions and molecular oxygen. Here we show that the iron-free protein does not undergo any major structural changes compared with the iron-containing R2. The effect of this is a clustering of four carboxyl side chains in the interior of the subunit, in contrast to the normal distribution of charged residues in proteins.