MAGPIE: A Machine Learning Approach to Decipher Protein-Protein Interactions in Human Plasma

Immunoprecipitation coupled to tandem mass spectrometry (IP-MS/MS) methods is often used to identify protein-protein interactions (PPIs). While these approaches are prone to false positive identifications through contamination and antibody nonspecific binding, their results can be filtered using negative controls and computational modeling. However, such filtering does not effectively detect false-positive interactions when IP-MS/MS is performed on human plasma samples. Therein, proteins cannot be overexpressed or inhibited, and existing modeling algorithms are not adapted for execution without such controls. Hence, we introduce MAGPIE, a novel machine learning-based approach for identifying PPIs in human plasma using IP-MS/MS, which leverages negative controls that include antibodies targeting proteins not expected to be present in human plasma. A set of negative controls used for false positive interaction modeling is first constructed. MAGPIE then assesses the reliability of PPIs detected in IP-MS/MS experiments using antibodies that target known plasma proteins. When applied to five IP-MS/MS experiments as a proof of concept, our algorithm identified 68 PPIs with an FDR of 20.77%. MAGPIE significantly outperformed a state-of-the-art PPI discovery tool and identified known and predicted PPIs. Our approach provides an unprecedented ability to detect human plasma PPIs, which enables a better understanding of biological processes in plasma.