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SAR by MS for Functional Genomics (Structure-Activity Relation by Mass Spectrometry)
Bruce Randall Donald, Chris Bailey-Kellogg, John J. Kelley, Clifford Stein
Dartmouth PCS-TR99-359


Large-scale functional genomics will require fast, high-throughput experimental techniques, coupled with sophisticated computer algorithms for data analysis and experiment planning. In this paper, we introduce a combined experimental-computational protocol called Structure-Activity Relation by Mass Spectrometry (SAR by MS), which can be used to elucidate the function of protein-DNA or protein-protein complexes. We present algorithms for SAR by MS and analyze their complexity. Carefully-designed Matrix-Assisted Laser Desorption/Ionization Time-Of-Flight (MALDI TOF) and Electrospray Ionization (ESI) assays require only femtomolar samples, take only microseconds per spectrum to record, enjoy a resolution of up to one dalton in $10^6$, and (in the case of MALDI) can operate on protein complexes up to a megadalton in mass. Hence, the technique is attractive for high-throughput functional genomics.

In SAR by MS, selected residues or nucleosides are 2H-, 13C-, and/or 15N-labeled. Second, the complex is crosslinked. Third, the complex is cleaved with proteases and/or endonucleases. Depending on the binding mode, some cleavage sites will be shielded by the crosslinking. Finally, a mass spectrum of the resulting fragments is obtained and analyzed. The last step is the Data Analysis phase, in which the mass signatures are interpreted to obtain constraints on the functional binding mode. Experiment Planning entails deciding what labeling strategy and cleaving agents to employ, so as to minimize mass degeneracy and spectral overlap, in order that the constraints derived in data analysis yield a small number of binding hypotheses.

A number of combinatorial and algorithmic questions arise in deriving algorithms for both Experiment Planning and Data Analysis. We explore the complexity of these problems, obtaining upper and lower bounds. Experimental results are reported from an implementation of our algorithms.

Note: This report is superceded by TR2000-362 .

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   Bruce Randall Donald, Chris Bailey-Kellogg, John J. Kelley, and Clifford Stein, "SAR by MS for Functional Genomics (Structure-Activity Relation by Mass Spectrometry)." Dartmouth Computer Science Technical Report PCS-TR99-359, October 1999.

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