Many but not all iron–sulphur clusters in metalloproteins are known to be sensitive to molecular oxygen with dramatic consequences for their biological function. We performed a systematic quantum chemical investigation that sheds light on the differences in oxygen sensitivity depending on charge and spin states of these clusters as well as on their spatial fixation by the enzyme's scaffold. We find that significant structural distortions are required to bind O₂ exothermically to [Fe₂S₂] and [Fe₃S₄] clusters, while only small conformational changes allow for the thermodynamically favorable coordination of molecular oxygen to [Fe₄S₄] cubanes and [Fe₄S₃] clusters.