SWAPS: A Modular Deep-Learning Empowered Peptide Identity Propagation Framework Beyond Match-Between-Run

Mass spectrometry (MS)-based proteomics relies heavily on MS/MS (MS2) data, which do not fully exploit the available MS1 information. Traditional peptide identity propagation (PIP) methods, such as match-between-runs (MBR), are limited to similar runs, particularly with the same liquid chromatography (LC) gradients, thus potentially underutilizing available proteomics libraries. We introduce SWAPS, a novel and modular MS1-centric framework incorporating advances in peptide property prediction, extensive proteomics libraries, and deep-learning-based postprocessing to enable and explore PIP across more diverse experimental conditions and LC gradients. SWAPS substantially enhances precursor identification, especially in shorter gradients. On the example of 30, 15, and 7.5 min gradients, SWAPS achieves increases of 46.3, 86.2, and 112.1% on precursor level over MaxQuant’s MS2-based identifications. Despite the inherent challenges in controlling false discovery rates (FDR) with MS1-based methods, SWAPS demonstrates strong efficacy in deconvoluting MS1 signals, offering powerful discrimination and deeper sequence exploration, while maintaining quantitative accuracy. By building on and applying peptide property predictions in practical contexts, SWAPS reveals that current models, while advanced, are still not fully comparable to experimental measurements, sparking the need for further research. Additionally, its modular design allows seamless integration of future improvements, positioning SWAPS as a forward-looking tool in proteomics.