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Fidelity of seryl-tRNA synthetase to binding of natural amino acids from HierDock first principles computations

McClendon, Christopher L. and Vaidehi, Nagarajan and Kam, Victor Wai Tak and Zhang, Deqiang and Goddard, William A., III (2006) Fidelity of seryl-tRNA synthetase to binding of natural amino acids from HierDock first principles computations. Protein Engineering, Design and Selection, 19 (5). pp. 195-203. ISSN 1741-0126.

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Seryl-tRNA synthetase (SerRS) charges serine to tRNA^(Ser) 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.

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Goddard, William A., III0000-0003-0097-5716
Additional Information:© The Author 2006. Published by Oxford University Press. Received August 22, 2005. Accepted January 31, 2006. Revision received December 24, 2005. First published online: March 3, 2006. Edited by Dieter Söll. We thank Mr Ismet Caglar Tanrikulu for much assistance in developing the methodology and software tools to aid in calculating the binding energy in the activating mode. We also thank Dr Wely B.Floriano, Mr Peter Freddolino and Dr Rene J.Trabanino for additional assistance and valuable advice. Mr C.L.M. was funded in part by Mr and Mrs Donald M. Alstadt as part of the Summer Undergraduate Research Fellowship (SURF) program at Caltech. This research was also funded by CSEM (NSF MRSEC) and NIH. Molecular graphics presented in this paper were prepared using QUANTA (1998 Molecular Simulations, Inc.) and PyMOL (DeLano, 2002). The facilities of the Materials and Process Simulation Center at Caltech (MSC) used for this work were supported by grants from DURIP-ARODURIP-ONR, IBM-SER and the Beckman Institute.
Funding AgencyGrant Number
Caltech Summer Undergraduate Research Fellowship (SURF)UNSPECIFIED
NSF Materials Research Science and Engineering Centers (MRSEC)UNSPECIFIED
Defense University Research Instrumentation Program (DURIP)-Army Research Office (ARO)UNSPECIFIED
Defense University Research Instrumentation Program (DURIP)-Office of Naval Reseach (ONR)UNSPECIFIED
Beckman InstituteUNSPECIFIED
Subject Keywords:aminoacyl-tRNA synthetase; fidelity of protein synthesis; HierDock, SCREAM; seryl-tRNA synthetase
Issue or Number:5
Record Number:CaltechAUTHORS:20110711-100506607
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Official Citation: Christopher L. McClendon, Nagarajan Vaidehi, Victor Wai Tak Kam, Deqiang Zhang, and William A. Goddard III Fidelity of seryl-tRNA synthetase to binding of natural amino acids from HierDock first principles computations Protein Engineering, Design and Selection (May 2006) 19(5): 195-203 doi:10.1093/protein/gzl001
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:24353
Deposited By: Ruth Sustaita
Deposited On:11 Jul 2011 18:15
Last Modified:26 Nov 2019 11:15

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