O’Reilly Lab

We develop crosslinking mass spectrometry approaches to define how protein complexes are organized, remodeled and regulated inside cells. Our lab works at the interface of structural biology, proteomics, chemical biology and integrative modeling. We combine experimental method development with computational approaches to map physical contacts between proteins and convert that information into protein interaction networks.

We are especially interested in interactions that are difficult to capture by conventional approaches, including transient regulatory interfaces, weak or low-abundance interactions and complexes that depend on native cellular conditions. These interactions are often lost when cells are disrupted, but they are central to the function and regulation of many molecular machines. By developing new crosslinking chemistries, in situ mass spectrometry workflows and computational strategies, we aim to understand how protein contacts are organized, remodeled and rewired across biological contexts and to discover new therapeutic vulnerabilities that are difficult to access by conventional structural biology alone.

A central goal of our lab is to help make in situ structural proteomics a rigorous and broadly useful approach for studying native protein interaction networks. We place strong emphasis on data reliability, including statistical control of false discoveries, quantitative benchmarking and integration with complementary structural methods such as cryo-electron microscopy, cryo-electron tomography, crystallography and AI-assisted modeling.

Dr. O’Reilly is a structural biologist who received his master’s degree in molecular biology from the University of Edinburgh, followed by a PhD in molecular and systems biology from the European Molecular Biology Laboratory, Heidelberg, Germany. He then moved to Berlin, Germany, where he completed a postdoctoral fellowship in structural proteomics at Technische Universität Berlin. Dr. O’Reilly then accepted a position as a Stadtman Tenure-Track Investigator at the National Cancer Institute, where he led a team focused on using structural biology and proteomics to address biological questions related to cancer biology and the gut microbiome. 

In 2025, Dr. O’Reilly joined St. Jude as an Assistant Member in the Department of Structural Biology and the Center of Excellence for Data-Driven Discovery. He has made key contributions to the field of structural proteomics — developing, optimizing and generalizing frameworks for chemical cross-linking and mass spectrometry methodologies. At St. Jude, Dr. O’Reilly’s team is investigating in situ protein interaction networks, specifically transient molecular interfaces and how those relate to health and disease.