The technique of model-building a protein of known sequence but unknow
n tertiary structure from the structures of homologous proteins is pro
bably so far the most reliable means of mapping from primary to tertia
ry structure. A key step towards the realization of the aim is to deve
lop ways of aligning three-dimensional structures of homologous protei
ns, thereby deriving the rules useful for protein modelling. We have d
eveloped a generalized differential-geometric representation of protei
n local conformation for use in a protein comparison program which ali
gns protein sequences on the basis of their sequence and conformationa
l knowledge. Because the differential-geometric distance measure betwe
en local conformations is independent of the coordinate frame and rema
ins chirality information, the comparison program is easily implemente
d, relatively rational and reasonably fast. The utility of this progra
m for aligning closely and distantly related homologous proteins is de
monstrated by multiple alignment of globins, serine proteinases and as
partic proteinase domains. Particularly, the method has reached the ra
tional alignment between the mammalian and microbial serine proteinase
s as compared with many published alignment programs.