An iterative structure-assisted approach to sequence alignment and comparative modeling

Correct alignment of the sequence of a target protein with those of homolog ues of known three-dimensional structure is a key step in comparative model ing. Usually an iterative approach that takes account of the local and over all structural features is required. We describe such an approach that expl oits databases of structural alignments of homologous proteins (HOMSTRAD, h ttp://www-cryst.bioc.cam.ac.uk/similar to homstrad) and protein superfamili es (CAMPASS, http://www-cryst.bioc. cam.ac.uk/similar to campass), in which structure-based alignments are analyzed and formatted with the program JOY (http://www-cryst.bioc.cam.ac.uk/similar to joy) to reveal conserved local structural features. The databases facilitate the recognition of a family or superfamily, they assist in the selection of useful parent structures, t hey are helpful in alignment of the target sequences with the parent set, a nd are useful for deriving relationships that can be used in validating mod els, In the iterative approach, a model is constructed on the basis of the proposed sequence alignment and this is then reexpressed in the JOY format and realigned with the parent set. This is repeated until the model and seq uence alignment is optimized, We examine the case for comparison and use of multiple structures of family members, rather than a single parent structu re. We use the targets attempted by our group in GASPS to assess the value of such procedures. (C) 1999 Wiley Liss, Inc.