TY - JOUR
T1 - Using protein design for homology detection and active site searches
AU - Pei, Jimin
AU - Dokholyan, Nikolay V.
AU - Shakhnovich, Eugene I.
AU - Grishin, Nick V.
PY - 2003/9/30
Y1 - 2003/9/30
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=0141705410&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0141705410&partnerID=8YFLogxK
U2 - 10.1073/pnas.2034878100
DO - 10.1073/pnas.2034878100
M3 - Article
C2 - 12975528
AN - SCOPUS:0141705410
SN - 0027-8424
VL - 100
SP - 11361
EP - 11366
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 20
ER -