PEDS Advance Access published online on March 3, 2006
Protein Engineering Design and Selection, doi:10.1093/protein/gzl001
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1 Materials and Process Simulation Center, California Institute of Technology, Pasadena, CA 91125, USA; Present address: Graduate Group in Biophysics, University of California San Francisco, San Francisco, CA, USA
* To whom correspondence should be addressed. Seryl-tRNA synthetase (SerRS) charges serine to tRNASer following the formation of a seryl adenylate intermediate, but the extent to which other non-cognate amino acids compete with serine to bind to SerRS or for the formation of the activated seryl adenylate intermediate is not known. To examine the mechanism of discrimination against non-cognate amino acids, we calculated the relative binding energies of the 20 natural amino acids to SerRS. Starting with the crystal structure of SerRS from Thermus thermophilus with seryl adenylate bound, we used the HierDock and SCREAM (Side-Chain Rotamer Energy Analysis Method) computational methods to predict the binding conformation and binding energy of each of the 20 natural amino acids in the binding site in the best-binding mode and the activating mode. The ordering of the calculated binding energies in the activated mode agrees with kinetic measurements in yeast SerRS that threonine will compete with serine for formation of the activated intermediate while alanine and glycine will not compete significantly. In addition, we predict that asparagine will compete with serine for formation of the activated intermediate. Experiments to check the accuracy of this prediction would be useful in further validating the use of HierDock and SCREAM for designing novel amino acids to incorporate into proteins and for determining mutations in aminoacyl-tRNA synthetase design to facilitate the incorporation of amino acid analogs into proteins.
Received August 22, 2005
Revised December 24, 2005
Accepted January 31, 2006
Article
Fidelity of seryl-tRNA synthetase to binding of natural amino acids from HierDock first principles computations
Christopher L. McClendon 1,
Nagarajan Vaidehi 2,
Victor Wai Tak Kam 2,
Deqiang Zhang 3,
and
William A. Goddard III 2 *
2 Materials and Process Simulation Center, California Institute of Technology, Pasadena, CA 91125, USA
3 Materials and Process Simulation Center, California Institute of Technology, Pasadena, CA 91125, USA; Present address: Howard Hughes Medical Institute and Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, CA, USA
William A. Goddard III, E-mail: wag{at}wag.caltech.edu
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