Generative and interpretable machine learning for aptamer design and analysis of in vitro sequence selection

Andrea Di Gioacchino, Jonah Procyk, Marco Molari, John S Schreck, Yu Zhou, Yan Liu, Rémi Monasson, Simona Cocco and Petr Šulc

PLOS Computational Biology, 2022, vol. 18, issue 9, 1-31

Abstract: Selection protocols such as SELEX, where molecules are selected over multiple rounds for their ability to bind to a target of interest, are popular methods for obtaining binders for diagnostic and therapeutic purposes. We show that Restricted Boltzmann Machines (RBMs), an unsupervised two-layer neural network architecture, can successfully be trained on sequence ensembles from single rounds of SELEX experiments for thrombin aptamers. RBMs assign scores to sequences that can be directly related to their fitnesses estimated through experimental enrichment ratios. Hence, RBMs trained from sequence data at a given round can be used to predict the effects of selection at later rounds. Moreover, the parameters of the trained RBMs are interpretable and identify functional features contributing most to sequence fitness. To exploit the generative capabilities of RBMs, we introduce two different training protocols: one taking into account sequence counts, capable of identifying the few best binders, and another based on unique sequences only, generating more diverse binders. We then use RBMs model to generate novel aptamers with putative disruptive mutations or good binding properties, and validate the generated sequences with gel shift assay experiments. Finally, we compare the RBM’s performance with different supervised learning approaches that include random forests and several deep neural network architectures.Author summary: We show that two-layer neural networks, Restricted Boltzmann Machines (RBM), can be successfully trained on sequence ensemble datasets from selection-amplification experiments. We train the RBM using datasets from aptamer selection experiments on thrombin protein, and show that the model can successfully generalize to the test set to predict binders and non-binders. The log-likelihood assigned to a sequence by the RBM is correlated with the sequence fitness as quantified by the amplification between different rounds of selection. We further show that that the model is interpretable and by inspecting the weights of the model, we can identify structural motifs that are characteristic of the good binders. We explore the usage of the RBMs to identify which of the possible protein exosites the aptamers bind to. We show that the RBM can also be used for unsupervised clustering. Finally, we use RBMs to generate novel aptamers, and we experimentally verify predicted binding and non-binding sequences generated from the RBM.

Date: 2022
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Persistent link: https://EconPapers.repec.org/RePEc:plo:pcbi00:1010561

DOI: 10.1371/journal.pcbi.1010561

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