RT Journal Article
SR Electronic
T1 Analysis of Independent Differences (AID) detects complex thermal proteome profiles independent of shape and identifies candidate panobinostat targets
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 751818
DO 10.1101/751818
A1 Alexandra Panov
A1 Steven P. Gygi
YR 2019
UL http://biorxiv.org/content/early/2019/08/31/751818.abstract
AB Identifying global cellular targets of small molecules is a challenge for drug discovery. Thermal proteome profiling (TPP) is a recent technique that uses quantitative proteomics to identify all small molecule protein targets in a single experiment. One current TPP analysis method relies on two major assumptions: sigmoidal melting curve behavior and that intra-condition dependencies preclude an independent and identically distributed model. Herein, we use a previously published panobinostat TPP dataset to show that these assumptions do not hold true and present a novel, shape-independent method, named Analysis of Independent Differences (AID). For each temperature, AID models the differences between conditions of fractions of non-denatured protein as an independent Normal distribution, resulting in a Multivariate Normal observation for each protein. The log of a Multivariate Normal p-value ranks the proteins from most to least likely shifted, and individual Normal p-values within each protein allow for qualitative inspection. Applying AID to the panobinostat dataset revealed known targets in the top 3% of most shifted proteins, as well as candidate targets involved in myeloid leukocyte activation. AID detects complex melting profiles and can be extended to any number of temperature channels, ligand-protein or protein-protein interactions, or general curve data for deeper biological insight.