Ion Mobility Mass Spectrometry Guided Modeling with AlphaFold and Rosetta Improves Protein Complex Structure Prediction

Ion mobility mass spectrometry (IM-MS) provides valuable structural information about protein shape and size through collision cross section (CCS). However, it lacks atomic level structural detail. While AlphaFold has been successful in predicting monomeric protein structure, it can struggle with modeling protein complexes. To address these limitations, we developed a method that integrates IM-MS data with AlphaFold and Rosetta to improve complex structure prediction. Our approach uses experimental CCS data to guide the assembly of AlphaFold predicted subunits using a Rosetta docking pipeline and evaluating the resulting complexes with a newly developed score. Using this strategy, we were able to improve root mean square deviation (RMSD) values for 26 of 38 (68%) complexes compared to AlphaFold-Multimer. Furthermore, 16 of these systems improved significantly from greater than 4 Å RMSD to less than 4 Å. This method demonstrates a robust approach to overcome limitations in complex assembly modeling.