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Using protein design for homology detection and active site searches.


ABSTRACT: We describe a method of designing artificial sequences that resemble naturally occurring sequences in terms of their compatibility with a template structure and its functional constraints. The design procedure is a Monte Carlo simulation of amino acid substitution process. The selective fixation of substitutions is dictated by a simple scoring function derived from the template structure and a multiple alignment of its homologs. Designed sequences represent an enlargement of sequence space around native sequences. We show that the use of designed sequences improves the performance of profile-based homology detection. The difference in position-specific conservation between designed sequences and native sequences is helpful for prediction of functionally important residues. Our sequence selection criteria in evolutionary simulations introduce amino acid substitution rate variation among sites in a natural way, providing a better model to test phylogenetic methods.

SUBMITTER: Pei J 

PROVIDER: S-EPMC208762 | biostudies-literature | 2003 Sep

REPOSITORIES: biostudies-literature

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Using protein design for homology detection and active site searches.

Pei Jimin J   Dokholyan Nikolay V NV   Shakhnovich Eugene I EI   Grishin Nick V NV  

Proceedings of the National Academy of Sciences of the United States of America 20030915 20


We describe a method of designing artificial sequences that resemble naturally occurring sequences in terms of their compatibility with a template structure and its functional constraints. The design procedure is a Monte Carlo simulation of amino acid substitution process. The selective fixation of substitutions is dictated by a simple scoring function derived from the template structure and a multiple alignment of its homologs. Designed sequences represent an enlargement of sequence space aroun  ...[more]

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