Proteins have evolved under selective pressure to carry out speciﬁc functions, and all of those functions depend, in one way or another, on interactions with other molecules. The way in which a protein interacts with the molecules in its environment depends critically on its three-dimensional structure or fold-the overall shape, the presence of clefts and cavities that complement particular ligands or substrates, the distribution of charges internally and over the surface, and the positioning of key amino acid residues. This book is not the place to ﬁnd a detailed account of the principles of protein structure, although a brief overview is provided in Box 6.1 and additional sources of information can be found in the Further Reading section. The important point here is that proteins with similar structures often have similar functions. Structures, like sequences, therefore have a predictive value in the assignment of protein functions.