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Bioinformatics Advance Access published online on September 25, 2007
Bioinformatics, doi:10.1093/bioinformatics/btm406
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© The Author (2007). Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Minimizing The Overlap Problem In Protein NMR: A Computational Framework For Precision Amino Acid Labeling

Michael J. Sweredoski a,c, Kevin J. Donovan b,c, Bao Nguyen b, A.J. Shaka b,c and Pierre Baldi a,c,*

aComputer Science Department, U.C. Irvine, bDepartment of Chemistry, U.C. Irvine, cInstitute for Genomics and Bioinformatics

*To whom correspondence should be addressed. Pierre Baldi, E-mail: pfbaldi{at}ics.uci.edu


  Abstract

Motivation: Recent advances in cell-free protein expression systems allow specific labeling of proteins with amino acids containing stable isotopes (15N, 13C, and 2H), an important feature for protein structure determination by nuclear magnetic resonance (NMR) spectroscopy. Given this labeling ability, we present a mathematical optimization framework for designing a set of protein isotopomers, or labeling schedules, to reduce the congestion in the NMR spectra. The labeling schedules, which are derived by the optimization of a cost function, are tailored to a specific protein and NMR experiment.

Results: For 2D 15N-1H HSQC experiments, we can produce an exact solution using a dynamic programming algorithm in under two hours on a standard desktop machine. Applying the method to a standard benchmark protein, calmodulin, we are able to reduce the number of overlaps in the 500MHz HSQC spectrum from ten to one using four samples with a true cost function, and ten to four if the cost function is derived from statistical estimates. On a set of 448 curated proteins from the BMRB database, we are able to reduce the relative percent congestion by 84.9% in their HSQC spectra using only four samples. Our method can be applied in a high-throughput manner on a proteomic scale using the server we developed. On a 100 node cluster, optimal schedules can be computed for every protein coded for in the human genome in less than a month.

Availability: A server for creating labeling schedules for 15N-1H HSQC experiments as well as results for each of the individual 448 proteins used in the test set is available at http://www.ics.uci.edu/~baldig/NMR/.

Contact pfbaldi{at}ics.uci.edu

Associate Editor: Prof. Burkhard Rost

Received on April 21, 2007; revised on July 6, 2007; accepted on August 6, 2007

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