ITLApplied  Computational Mathematics Division
ACMD Seminar Series
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Amino acid exchangeability from experimental data

Arlin Stoltzfus
Center for Advanced Research in Biotechnology, NIST

Tuesday, April 9, 2002 15:00-16:00,
Room 145, NIST North (820)
Tuesday, April 9, 2002 13:00-14:00,
Room 4511

Abstract: Patterns of amino acid sequence change in proteins are often interpreted by reference to a pairwise measure of amino acid distance, based either on some biophysical model of effects, or more commonly on propensities of evolutionary change. Though both types of measure are useful, the first is based on an uncertain estimation of the role of amino acid chemistry in a protein environment, and the second, though it naturally reflects this role, confounds protein effects with unrelated evolutionary factors, particularly genetic mutation between codons. To separate the exchangeability of amino acids in proteins from effects of the mutational interchangeability of codons, a measure of amino acid exchangeability has been computed from results of 9695 experimental amino acid exchanges from 12 experimental studies in which amino acids were exchanged systematically. A frequency distribution of the quantitative effects of amino acid exchanges on protein activity is derived from the data and used as the basis for transforming results of different studies to a common scale. Combining the results of all 12 studies yields a nearly complete matrix of exchangeability, here called EX. The power of this measure has been evaluated, in comparison to available measures of amino acid distance, by a jack-knife procedure in which 11 studies are used to predict the results of the 12th study. In limited tests done so far, EX out-performs commonly used alternatives, including divergence- based matrices (PAM, BLOSUM), an ad hoc matrix based on physicochemical properties of amino acids (Grantham), and a physics-based model of mean effect estimated from structural data (Miyazawa-Jernigan). In combination with models of the mutation spectrum, EX may prove useful in teasing apart the separate influences of mutation and selection on codon usage, amino acid composition, and protein sequence evolution.
Contact: F. Hunt

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