Abstract

The ‘inverse problem’ of mass spectrometric molecular identification (‘given a mass spectrum, calculate/predict the 2D structure of the molecule whence it came’) is largely unsolved, and is especially acute in metabolomics where many small molecules remain unidentified. This is largely because the number of experimentally available electrospray mass spectra of small molecules is quite limited. However, the forward problem (‘calculate a small molecule’s likely fragmentation and hence at least some of its mass spectrum from its structure alone’) is much more tractable, because the strengths of different chemical bonds are roughly known. This kind of molecular identification problem may be cast as a language translation problem in which the source language is a list of high-resolution mass spectral peaks and the ‘translation’ a representation (for instance in SMILES) of the molecule. It is thus suitable for attack using the deep neural networks known as transformers. We here present MassGenie, a method that uses a transformer-based deep neural network, trained on ~6 million chemical structures with augmented SMILES encoding and their paired molecular fragments as generated in silico, explicitly including the protonated molecular ion. This architecture (containing some 400 million elements) is used to predict the structure of a molecule from the various fragments that may be expected to be observed when some of its bonds are broken. Despite being given essentially no detailed nor explicit rules about molecular fragmentation methods, isotope patterns, rearrangements, neutral losses, and the like, MassGenie learns the effective properties of the mass spectral fragment and valency space, and can generate candidate molecular structures that are very close or identical to those of the ‘true’ molecules. We also use VAE-Sim, a previously published variational autoencoder, to generate candidate molecules that are ‘similar’ to the top hit. In addition to using the ‘top hits’ directly, we can produce a rank order of these by ‘round-tripping’ candidate molecules and comparing them with the true molecules, where known. As a proof of principle, we confine ourselves to positive electrospray mass spectra from molecules with a molecular mass of 500Da or lower, including those in the last CASMI challenge (for which the results are known), getting 49/93 (53%) precisely correct. The transformer method, applied here for the first time to mass spectral interpretation, works extremely effectively both for mass spectra generated in silico and on experimentally obtained mass spectra from pure compounds. It seems to act as a Las Vegas algorithm, in that it either gives the correct answer or simply states that it cannot find one. The ability to create and to ‘learn’ millions of fragmentation patterns in silico, and therefrom generate candidate structures (that do not have to be in existing libraries) directly, thus opens up entirely the field of de novo small molecule structure prediction from experimental mass spectra.

Highlights

  • The measurement of small molecules within biological matrices, commonly referred to as metabolomics [1,2], is an important part of modern post-genomics

  • The first task was to train the deep transformer network described in Methods with paired in silico mass spectra as inputs and molecular structures as outputs

  • We used a validation set of 100,000 molecules and use the performance achieved on that set as a metric to ascertain that we use the best version of the trained model for the testing

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Summary

Introduction

The measurement of small molecules within biological matrices, commonly referred to as metabolomics [1,2], is an important part of modern post-genomics. For the deconvolution of matrices such as human serum, chromatography methods coupled to mass spectrometry are pre-eminent [3,4]. In mass spectrometry (MS), molecules are ionised and enter a gas phase, commonly using electrospray methods, and the masses and intensities of the fragments—the mass spectrum—contains the diagnostic information that in principle represents a fingerprint for identifying the target molecule of interest. Identification is currently largely performed by comparing the peaks in the mass spectra obtained with those in a library of mass spectra from known molecules, and the identities may be confirmed by running authentic chemical standards, if available

Methods
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