The FASEB Journal, Vol 10, 126-136, Copyright © 1996 by The Federation of American Societies for Experimental Biology

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Assigning amino acid sequences to 3-dimensional protein folds

D Fischer, D Rice, JU Bowie and D Eisenberg
UCLA-DOE Laboratory of Structural Biology and Molecular Medicine, Molecular Biology Institute 90095-1570, USA.

With the advent of genome sequencing projects, the amino acid sequences of thousands of proteins are determined every year. Each of these protein sequences must be identified with its function and its 3- dimensional structure for us to gain a full understanding of the molecular biology of organisms. To meet this challenge, new methods are being developed for fold recognition, the computational assignment of newly determined amino acid sequences to 3-dimensional protein structures. These methods start with a library of known 3-dimensional target protein structures. The new probe sequence is then aligned to each target protein structure in the library and the compatibility of the sequence for that structure is scored. If a target structure is found to have a significantly high compatibility score, it is assumed that the probe sequence folds in much the same way as the target structure. The fundamental assumptions of this approach are that many different sequences fold in similar ways and there is a relatively high probability that a new sequence possesses a previously observed fold. We review various approaches to fold recognition and break down the process into its main steps: creation of a library of target folds; representation of the folds; alignment of the probe sequence to a target fold using a sequence-to-structure compatibility scoring function; and assessment of significance of compatibility. We emphasize that even though this new field of fold recognition has made rapid progress, technical problems remain to be solved in most of the steps. Standard benchmarks may help identify the problem steps and find solutions to the problems.

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