Rosetta Protein Structure Prediction from Hydroxyl Radical Protein Footprinting Mass Spectrometry Data

By Melanie L. Aprahamian, Emily E. Chea, L. Jones, Steffen Lindert. 2018

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In recent years mass spectrometry-based covalent labeling techniques such as hydroxyl radical footprinting (HRF) have emerged as valuable structural biology techniques yielding information on protein tertiary structure. This data, however, is not sufficient to predict protein structure unambiguously, as it only provides information on the relative solvent exposure of certain residues. Despite some recent advances, no software currently exists that can utilize covalent labeling mass spectrometry data to predict protein tertiary structure. We have developed the first such tool, which incorporates mass spectrometry derived protection factors from HRF labeling as a new centroid score term for the Rosetta scoring function to improve the prediction of protein tertiary structure. We tested our method on a set of four soluble benchmark proteins with known crystal structures and either published HRF experimental results or internally acquired data. Using the HRF labeling data, we rescored large decoy sets of structures predicted with Rosetta for each of the four benchmark proteins. As a result, the model quality improved for all benchmark proteins, as compared to when scored with Rosetta alone. For two of the four proteins, we were even able to identify atomic resolution models with the addition of HRF data.

Subfields: Molecular Biology, Spectroscopy