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Updated: Aug 9, 2026

A Protocol for Computer-Based Protein Structure and Function Prediction
Published on: November 3, 2011
Using protein design for homology detection and active site searches
Jimin Pei1, Nikolay V Dokholyan, Eugene I Shakhnovich
1Department of Biochemistry and Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
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.
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