Xiuxia Du

Xujun Che, Xiuxia Du, Depeng Xu

De novo molecular generation from tandem mass spectra is a challenging inverse problem whose core difficulty lies in the circular dependency between atom-level and bond-level reasoning: determining a bond's type requires knowing its endpoint atoms' chemical environment, yet an atom's environment is in turn defined by its incident bonds. Existing graph diffusion methods process atoms and bonds within a single computation stream, where atom-bond information synchronization can only occur implicitly across layers. We argue that this single-stream paradigm, rather than the choice of any particular aggregation kernel, is a key architectural bottleneck. We propose DualLGD (Dual-stream Line Graph Diffusion), which reformulates molecular graph denoising as the alternating solution of two coupled subproblems: atom-level reasoning and bond-level reasoning, each operating in its own dedicated representation space. The line graph provides a natural mathematical construction for the bond space, in which bond angles, dihedrals, conjugation chains, and rings correspond to local topological motifs between bonds. Incidence-constrained bidirectional cross-attention synchronizes the two streams at every layer, ensuring that each atom attends only to its incident bonds and vice versa, respecting the fundamental chemical principle that an atom's environment is determined by its bonding context. On the NPLIB1 and MassSpecGym benchmarks, DualLGD achieves top-1 accuracy of 34.37\% and 23.89\%, approximately $3\times$ the previous state of the art. Ablation studies confirm the architecture as the primary source of improvement: DualLGD without any pre-training already surpasses the previous best fully pretrained model.

Xujun Che, Xiuxia Du, Depeng Xu

Liquid chromatography mass spectrometry (LC-MS)-based metabolomics and exposomics aim to measure detectable small molecules in biological samples. The results facilitate hypothesis-generating discovery of metabolic changes and disease mechanisms and provide information about environmental exposures and their effects on human health. Metabolomics and exposomics are made possible by the high resolving power of LC and high mass measurement accuracy of MS. However, a majority of the signals from such studies still cannot be identified or annotated using conventional library searching because existing spectral libraries are far from covering the vast chemical space captured by LC-MS/MS. To address this challenge and unleash the full potential of metabolomics and exposomics, a number of computational approaches have been developed to predict compounds based on tandem mass spectra. Published assessment of these approaches used different datasets and evaluation. To select prediction workflows for practical applications and identify areas for further improvements, we have carried out a systematic evaluation of the state-of-the-art prediction algorithms. Specifically, the accuracy of formula prediction and structure prediction was evaluated for different types of adducts. The resulting findings have established realistic performance baselines, identified critical bottlenecks, and provided guidance to further improve compound predictions based on MS.