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Science 26 June 1992:
Vol. 256. no. 5065, pp. 1798 - 1802
DOI: 10.1126/science.1615324
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Articles

Science, Vol 256, Issue 5065, 1798-1802
Copyright © 1992 by American Association for the Advancement of Science

articles

Probing protein stability with unnatural amino acids

D Mendel, JA Ellman, Z Chang, DL Veenstra, PA Kollman, and PG Schultz

Department of Chemistry, University of California, Berkeley 94720.

Unnatural amino acid mutagenesis, in combination with molecular modeling and simulation techniques, was used to probe the effect of side chain structure on protein stability. Specific replacements at position 133 in T4 lysozyme included (i) leucine (wt), norvaline, ethylglycine, and alanine to measure the cost of stepwise removal of methyl groups from the hydrophobic core, (ii) norvaline and O-methyl serine to evaluate the effects of side chain solvation, and (iii) leucine, S,S-2-amino-4-methylhexanoic acid, and S-2-amino-3-cyclopentylpropanoic acid to measure the influence of packing density and side chain conformational entropy on protein stability. All of these factors (hydrophobicity, packing, conformational entropy, and cavity formation) significantly influence protein stability and must be considered when analyzing any structural change to proteins.


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