It is difficult to generalise which amino acids are likely to be in a protein active/functional site as this greatly depends on the type of function. With that in mind, below are preferences for the 20 amino acids to lie within functional regions on proteins (after Holm & Sander, Intelligent Systems for Molecular Biology, 5, 140-146, 1997). These were worked out by considering how often particular amino acids were in contact with bound non-protein atoms in protein three-dimensional structures. Postive values mean that the amino acid makes more contacts than one would expect by chance; negative values mean that it makes fewer. The below does not include protein-protein, or protein-peptide interactions, where many of the amino acids with negative values (e.g. tryptophan or proline) can play critical roles.