Systems and methods for proteomic activity analysis using DNA-encoded probes

A method for detecting proteomic activity in a sample comprising active proteins, the method comprising the steps of:

• providing a population of probes, each of the probes comprising a substrate linked to a DNA construct, the DNA construct comprising one or more amplifiable identification barcode regions, wherein at least one of the barcode regions of the double-stranded DNA is unique;
• contacting the population of probes with the sample comprising active proteins in an initial pool and under conditions and for a sufficient time to allow said protein to turnover via chemical transformation of the substrate of a probe into a product wherein the protein comprises a farnesyltransferase, a protein kinase, or a protease;
• quenching protein activity within the initial pool;
• combining the probes from multiple samples into an initial pool;
• separating the DNA probe constructs of the initial pool that are linked to the product or that are linked to the protein to form a purified pool, wherein the separating is performed by selectively linking a tag to said probes, wherein the tag is appended utilizing chemical or biochemical steps that selectively modify product molecules, but not substrate molecules, or wherein the tag is appended using chemical or biochemical steps that selectively modify substrate molecules, but not product molecules, and wherein the tag comprises a moiety for selective affinity purification;
• quantifying the DNA constructs of the initial pool and the DNA constructs of the purified pool by quantitative PCR, parallel DNA sequencing or high-throughput DNA sequencing;
• and
• detecting the presence or absence of a detectable signal in the quantified DNA constructs, the detectable signal comprising identifying a change in probe frequency between the initial pool and the purified pool.