SEVERAL model systems have been used to evaluate the alpha-helical pro
pensities of different amino acids(1-7). In contrast, experimental qua
ntitation of beta-sheet preferences has been addressed in only one mod
el system, a zinc-finger peptide(8). Here we measure the relative prop
ensity for beta-sheet formation of the twenty naturally occurring amin
o acids in a variant of the small, monomeric, beta-sheet-rich, IgG-bin
ding domain from protein G. Amino-acid substitutions were made at a gu
est site on the solvent-exposed surface of the beta-sheet. Several cri
teria were used to establish that the mutations did not cause signific
ant structural changes: binding to the Fc domain of IgG, calorimetric
unfolding and NMR spectroscopy. Characterization of the thermal stabil
ities of these proteins leads to a thermodynamic scale for beta-sheet
propensities that spans a range of similar to 2 kcal mol(-1) for the n
aturally occurring amino acids, excluding proline. The magnitude of th
e differences suggests that beta-sheet preferences can be important de
terminants of protein stability.