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Originally published as Genetics Published Articles Ahead of Print on June 8, 2005.
Genetics, Vol. 170, 1459-1472, August 2005, Copyright © 2005
doi:10.1534/genetics.104.039107
The Exchangeability of Amino Acids in Proteins
Lev Y. Yampolsky* and
Arlin Stoltzfus
,1
* Department of Biological Sciences, East Tennessee State University, Johnson City, Tennessee 37614-1710
Center for Advanced Research in Biotechnology, Rockville, Maryland 20850
1 Corresponding author: Center for Advanced Research in Biotechnology, 9600 Gudelsky Dr., Rockville, MD 20850.
E-mail: arlin.stoltzfus{at}nist.gov
The comparative analysis of protein sequences depends crucially on measures of amino acid similarity or distance. Many such measures exist, yet it is not known how well these measures reflect the operational exchangeability of amino acids in proteins, since most are derived by methods that confound a variety of effects, including effects of mutation. In pursuit of a pure measure of exchangeability, we present (1) a compilation of data on the effects of 9671 amino acid exchanges engineered and assayed in a set of 12 proteins; (2) a statistical procedure to combine results from diverse assays of exchange effects; (3) a matrix of "experimental exchangeability" values EXij derived from applying this procedure to the compiled data; and (4) a set of three tests designed to evaluate the power of an exchangeability measure to (i) predict the effects of amino acid exchanges in the laboratory, (ii) account for the disease-causing potential of missense mutations in the human population, and (iii) model the probability of fixation of missense mutations in evolution. EX not only captures useful information on exchangeability while remaining free of other effects, but also outperforms all measures tested except for the best-performing alignment scoring matrix, which is comparable in performance.
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