RosettaHDX: Predicting antibody-antigen interaction from hydrogen-deuterium exchange mass spectrometry data

Minh H Tran; Cristina E Martina; Rocco Moretti; Marcus Nagel; Kevin L Schey; Jens Meiler

doi:10.1016/j.jsb.2025.108166

RosettaHDX: Predicting antibody-antigen interaction from hydrogen-deuterium exchange mass spectrometry data

J Struct Biol. 2025 Jan 5;217(1):108166. doi: 10.1016/j.jsb.2025.108166. Online ahead of print.

Authors

Minh H Tran¹, Cristina E Martina², Rocco Moretti², Marcus Nagel³, Kevin L Schey⁴, Jens Meiler⁵

Affiliations

¹ Chemical and Physical Biology Program, Vanderbilt University, Nashville, TN, USA; Center of Structural Biology, Vanderbilt University, Nashville, TN, USA. Electronic address: [email protected].
² Center of Structural Biology, Vanderbilt University, Nashville, TN, USA; Department of Chemistry, Vanderbilt University, Nashville, TN, USA.
³ Mass Spectrometry Research Center, Department of Biochemistry, Vanderbilt University, Nashville, TN, USA.
⁴ Mass Spectrometry Research Center, Department of Biochemistry, Vanderbilt University, Nashville, TN, USA. Electronic address: [email protected].
⁵ Center of Structural Biology, Vanderbilt University, Nashville, TN, USA; Department of Chemistry, Vanderbilt University, Nashville, TN, USA; Institute for Drug Discovery, Institute for Computer Science, Wilhelm Ostwald Institute for Physical and Theoretical Chemistry, University Leipzig, Leipzig, Germany; Center for Scalable Data Analytics and Artificial Intelligence ScaDS.AI and School of Embedded Composite Artificial Intelligence SECAI, Dresden/Leipzig, Germany; Department of Pharmacology, Institute of Chemical Biology, Center for Applied Artificial Intelligence in Protein Dynamics, Vanderbilt University, Nashville, TN, USA. Electronic address: [email protected].

PMID: 39765317
DOI: 10.1016/j.jsb.2025.108166

Abstract

High-throughput characterization of antibody-antigen complexes at the atomic level is critical for understanding antibody function and enabling therapeutic development. Hydrogen-deuterium exchange mass spectrometry (HDX-MS) enables rapid epitope mapping, but its data are too sparse for independent structure determination. In this study, we introduce RosettaHDX, a hybrid method that combines computational docking with differential HDX-MS data to enhance the accuracy of antibody-antigen complex models beyond what either method can achieve individually. By incorporating HDX data as both distance restraints and a scoring term in the RosettaDock algorithm, RosettaHDX successfully generated near-native models (interface root-mean square deviation ≤ 4 Å) for all 9 benchmark complexes examined, averaging 3.6 times more near-native models than Rosetta alone. Near-native models among the top 10 scoring were identified in 3/9 cases, compared to 1/9 with Rosetta alone. Additionally, we developed a predictive metric based on docking results with HDX restraints to identify allosteric peptides in HDX datasets.

Keywords: Antibody-antigen interaction(2); Epitope-paratope identification(3); Hydrogen–deuterium exchange mass spectrometry (HDX-MS)(1); Integrative structural biology(6); Protein–protein docking(4); Structure modeling(5).