Background: By performing extensive pairwise structural comparisons, w
e recently identified a set of unique folds from the Brookhaven protei
n structure data bank. This analysis revealed considerable similaritie
s between a large subgroup of the alpha+beta folds, which led us to re
-examine the types of folds occurring in this class and the nature of
the relationships between them. Results: Two major alpha+beta fold gro
ups can be distinguished. In the first, described as alpha-beta sandwi
ches because alpha-helices and beta-strands occupy separate and distin
ct layers, a split beta alpha beta motif recurs frequently. The other
group, alpha-beta rolls, contains fewer helices and is more diverse. I
n these, the beta-sheet has folded or rolled over, providing a cradle
for the alpha-helix. A beta beta beta alpha-meander motif is found thr
oughout the alpha+beta class. Conclusion: Although many alpha-beta san
dwiches have very similar folds, few share common functions and the ac
tive sites are distributed over the whole surface of the fold. The abi
lity of the alpha-beta sandwich to accommodate a range of functions su
ggests that it is a stable fold and one that is able to adapt a number
of sites to satisfy different functional requirements. In contrast, a
mongst the alpha-beta rolls, folds having the same roll type often hav
e common functions.