Combining automated peak tracking in SAR by NMR with structure-based backbone assignment from 15N-NOESY
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Jang, RichardGao, Xin

Li, Ming

KAUST Department
Computational Bioscience Research Center (CBRC)Computer Science Program
Computer, Electrical and Mathematical Sciences and Engineering (CEMSE) Division
Structural and Functional Bioinformatics Group
Date
2012-03-22Online Publication Date
2012-03-22Print Publication Date
2012Permanent link to this record
http://hdl.handle.net/10754/325471
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Background: Chemical shift mapping is an important technique in NMR-based drug screening for identifying the atoms of a target protein that potentially bind to a drug molecule upon the molecule's introduction in increasing concentrations. The goal is to obtain a mapping of peaks with known residue assignment from the reference spectrum of the unbound protein to peaks with unknown assignment in the target spectrum of the bound protein. Although a series of perturbed spectra help to trace a path from reference peaks to target peaks, a one-to-one mapping generally is not possible, especially for large proteins, due to errors, such as noise peaks, missing peaks, missing but then reappearing, overlapped, and new peaks not associated with any peaks in the reference. Due to these difficulties, the mapping is typically done manually or semi-automatically, which is not efficient for high-throughput drug screening.Results: We present PeakWalker, a novel peak walking algorithm for fast-exchange systems that models the errors explicitly and performs many-to-one mapping. On the proteins: hBclXL, UbcH5B, and histone H1, it achieves an average accuracy of over 95% with less than 1.5 residues predicted per target peak. Given these mappings as input, we present PeakAssigner, a novel combined structure-based backbone resonance and NOE assignment algorithm that uses just 15N-NOESY, while avoiding TOCSY experiments and 13C-labeling, to resolve the ambiguities for a one-to-one mapping. On the three proteins, it achieves an average accuracy of 94% or better.Conclusions: Our mathematical programming approach for modeling chemical shift mapping as a graph problem, while modeling the errors directly, is potentially a time- and cost-effective first step for high-throughput drug screening based on limited NMR data and homologous 3D structures. 2012 Jang et al.; licensee BioMed Central Ltd.Citation
Jang R, Gao X, Li M (2012) Combining automated peak tracking in SAR by NMR with structure-based backbone assignment from 15N-NOESY. BMC Bioinformatics 13: S4. doi:10.1186/1471-2105-13-S3-S4.Publisher
Springer NatureJournal
BMC BioinformaticsPubMed ID
22536902PubMed Central ID
PMC3402924ae974a485f413a2113503eed53cd6c53
10.1186/1471-2105-13-S3-S4
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