Using protein design for homology detection and active site searches

Jimin Pei, Nikolay V. Dokholyan, Eugene I. Shakhnovich, Nick V. Grishin

Research output: Contribution to journalArticle

26 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)11361-11366
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume100
Issue number20
DOIs
StatePublished - Sep 30 2003

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Catalytic Domain
Amino Acid Substitution
Proteins
Patient Selection

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Using protein design for homology detection and active site searches. / Pei, Jimin; Dokholyan, Nikolay V.; Shakhnovich, Eugene I.; Grishin, Nick V.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 100, No. 20, 30.09.2003, p. 11361-11366.

Research output: Contribution to journalArticle

Pei, Jimin ; Dokholyan, Nikolay V. ; Shakhnovich, Eugene I. ; Grishin, Nick V. / Using protein design for homology detection and active site searches. In: Proceedings of the National Academy of Sciences of the United States of America. 2003 ; Vol. 100, No. 20. pp. 11361-11366.
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