Inferring residue-level hydrogen deuterium exchange with ReX

Author(s): Oliver Crook

Affiliation(s): University of Oxford



Hydrogen-Deuterium Exchange mass-spectrometry (HDX-MS) has emerged as a powerful technique to explore the conformational dynamics of proteins and protein complexes in solution. In the bottom-up approach to MS, deuterium uptake is reported at the level of peptides, which complicates interpretation and means ad-hoc approaches are used to resolve contradictions between overlapping peptides. Here we propose to leverage the overlap in peptides, the temporal component of the data and the correlation along the sequence dimension to infer residue-level uptake patterns. Our model treats HDX-MS as a multiple change-point problem - inferring at which residues HDX has changed. Fitting our model in the Bayesian non-parametric framework allows inference of the number of parameters, quantitative assessments of the confidence of differential HDX and uncertainty estimates of the temporal kinetics. We benchmark our approach against others using a three-way proteolytic digestion experiment and find that it out-performs other available methods. We illustrate our approach on a number of case-studies.