Retrosynthesis Prediction with Local Template Retrieval

Retrosynthesis, which predicts the reactants of a given target molecule, is an essential task for drug discovery. In recent years, the machine learing based retrosynthesis methods have achieved promising results. In this work, we introduce RetroKNN, a local reaction template retrieval method to further boost the performance of template-based systems with non-parametric retrieval. We first build an atom-template store and a bond-template store that contain the local templates in the training data, then retrieve from these templates with a k-nearest-neighbor (KNN) search during inference. The retrieved templates are combined with neural network predictions as the final output. Furthermore, we propose a lightweight adapter to adjust the weights when combing neural network and KNN predictions conditioned on the hidden representation and the retrieved templates. We conduct comprehensive experiments on two widely used benchmarks, the USPTO-50K and USPTO-MIT. Especially for the top-1 accuracy, we improved 7.1% on the USPTO-50K dataset and 12.0% on the USPTO-MIT dataset. These results demonstrate the effectiveness of our method.

MolXPT: Wrapping Molecules with Text for Generative Pre-training

Generative pre-trained Transformer (GPT) has demonstrates its great success in natural language processing and related techniques have been adapted into molecular modeling. Considering that text is the most important record for scientific discovery, in this paper, we propose MolXPT, a unified language model of text and molecules pre-trained on SMILES (a sequence representation of molecules) wrapped by text. Briefly, we detect the molecule names in each sequence and replace them to the corresponding SMILES. In this way, the SMILES could leverage the information from surrounding text, and vice versa. The above wrapped sequences, text sequences from PubMed and SMILES sequences from PubChem are all fed into a language model for pre-training. Experimental results demonstrate that MolXPT outperforms strong baselines of molecular property prediction on MoleculeNet, performs comparably to the best model in text-molecule translation while using less than half of its parameters, and enables zero-shot molecular generation without finetuning.

Filler Word Detection with Hard Category Mining and Inter-Category Focal Loss

Filler words like ``um" or ``uh" are common in spontaneous speech. It is desirable to automatically detect and remove them in recordings, as they affect the fluency, confidence, and professionalism of speech. Previous studies and our preliminary experiments reveal that the biggest challenge in filler word detection is that fillers can be easily confused with other hard categories like ``a" or ``I". In this paper, we propose a novel filler word detection method that effectively addresses this challenge by adding auxiliary categories dynamically and applying an additional inter-category focal loss. The auxiliary categories force the model to explicitly model the confusing words by mining hard categories. In addition, inter-category focal loss adaptively adjusts the penalty weight between ``filler" and ``non-filler" categories to deal with other confusing words left in the ``non-filler" category. Our system achieves the best results, with a huge improvement compared to other methods on the PodcastFillers dataset.

AMOM: Adaptive Masking over Masking for Conditional Masked Language Model

Transformer-based autoregressive (AR) methods have achieved appealing performance for varied sequence-to-sequence generation tasks, e.g., neural machine translation, summarization, and code generation, but suffer from low inference efficiency. To speed up the inference stage, many non-autoregressive (NAR) strategies have been proposed in the past few years. Among them, the conditional masked language model (CMLM) is one of the most versatile frameworks, as it can support many different sequence generation scenarios and achieve very competitive performance on these tasks. In this paper, we further introduce a simple yet effective adaptive masking over masking strategy to enhance the refinement capability of the decoder and make the encoder optimization easier. Experiments on \textbf{3} different tasks (neural machine translation, summarization, and code generation) with \textbf{15} datasets in total confirm that our proposed simple method achieves significant performance improvement over the strong CMLM model. Surprisingly, our proposed model yields state-of-the-art performance on neural machine translation (\textbf{34.62} BLEU on WMT16 EN$\to$RO, \textbf{34.82} BLEU on WMT16 RO$\to$EN, and \textbf{34.84} BLEU on IWSLT De$\to$En) and even better performance than the \textbf{AR} Transformer on \textbf{7} benchmark datasets with at least \textbf{2.2$\times$} speedup. Our code is available at GitHub.

Retrieved Sequence Augmentation for Protein Representation Learning

Protein language models have excelled in a variety of tasks, ranging from structure prediction to protein engineering. However, proteins are highly diverse in functions and structures, and current state-of-the-art models including the latest version of AlphaFold rely on Multiple Sequence Alignments (MSA) to feed in the evolutionary knowledge. Despite their success, heavy computational overheads, as well as the de novo and orphan proteins remain great challenges in protein representation learning. In this work, we show that MSAaugmented models inherently belong to retrievalaugmented methods. Motivated by this finding, we introduce Retrieved Sequence Augmentation(RSA) for protein representation learning without additional alignment or pre-processing. RSA links query protein sequences to a set of sequences with similar structures or properties in the database and combines these sequences for downstream prediction. We show that protein language models benefit from the retrieval enhancement on both structure prediction and property prediction tasks, with a 5% improvement on MSA Transformer on average while being 373 times faster. In addition, we show that our model can transfer to new protein domains better and outperforms MSA Transformer on de novo protein prediction. Our study fills a much-encountered gap in protein prediction and brings us a step closer to demystifying the domain knowledge needed to understand protein sequences. Code is available on https://github.com/HKUNLP/RSA.

De Novo Molecular Generation via Connection-aware Motif Mining

De novo molecular generation is an essential task for science discovery. Recently, fragment-based deep generative models have attracted much research attention due to their flexibility in generating novel molecules based on existing molecule fragments. However, the motif vocabulary, i.e., the collection of frequent fragments, is usually built upon heuristic rules, which brings difficulties to capturing common substructures from large amounts of molecules. In this work, we propose a new method, MiCaM, to generate molecules based on mined connection-aware motifs. Specifically, it leverages a data-driven algorithm to automatically discover motifs from a molecule library by iteratively merging subgraphs based on their frequency. The obtained motif vocabulary consists of not only molecular motifs (i.e., the frequent fragments), but also their connection information, indicating how the motifs are connected with each other. Based on the mined connection-aware motifs, MiCaM builds a connection-aware generator, which simultaneously picks up motifs and determines how they are connected. We test our method on distribution-learning benchmarks (i.e., generating novel molecules to resemble the distribution of a given training set) and goal-directed benchmarks (i.e., generating molecules with target properties), and achieve significant improvements over previous fragment-based baselines. Furthermore, we demonstrate that our method can effectively mine domain-specific motifs for different tasks.

Incorporating Pre-training Paradigm for Antibody Sequence-Structure Co-design

Antibodies are versatile proteins that can bind to pathogens and provide effective protection for human body. Recently, deep learning-based computational antibody design has attracted popular attention since it automatically mines the antibody patterns from data that could be complementary to human experiences. However, the computational methods heavily rely on high-quality antibody structure data, which is quite limited. Besides, the complementarity-determining region (CDR), which is the key component of an antibody that determines the specificity and binding affinity, is highly variable and hard to predict. Therefore, the data limitation issue further raises the difficulty of CDR generation for antibodies. Fortunately, there exists a large amount of sequence data of antibodies that can help model the CDR and alleviate the reliance on structure data. By witnessing the success of pre-training models for protein modeling, in this paper, we develop the antibody pre-training language model and incorporate it into the (antigen-specific) antibody design model in a systemic way. Specifically, we first pre-train an antibody language model based on the sequence data, then propose a one-shot way for sequence and structure generation of CDR to avoid the heavy cost and error propagation from an autoregressive manner, and finally leverage the pre-trained antibody model for the antigen-specific antibody generation model with some carefully designed modules. Through various experiments, we show that our method achieves superior performances over previous baselines on different tasks, such as sequence and structure generation and antigen-binding CDR-H3 design.

Improving Temporal Generalization of Pre-trained Language Models with Lexical Semantic Change

Recent research has revealed that neural language models at scale suffer from poor temporal generalization capability, i.e., the language model pre-trained on static data from past years performs worse over time on emerging data. Existing methods mainly perform continual training to mitigate such a misalignment. While effective to some extent but is far from being addressed on both the language modeling and downstream tasks. In this paper, we empirically observe that temporal generalization is closely affiliated with lexical semantic change, which is one of the essential phenomena of natural languages. Based on this observation, we propose a simple yet effective lexical-level masking strategy to post-train a converged language model. Experiments on two pre-trained language models, two different classification tasks, and four benchmark datasets demonstrate the effectiveness of our proposed method over existing temporal adaptation methods, i.e., continual training with new data. Our code is available at \url{https://github.com/zhaochen0110/LMLM}.

Unified 2D and 3D Pre-Training of Molecular Representations

Molecular representation learning has attracted much attention recently. A molecule can be viewed as a 2D graph with nodes/atoms connected by edges/bonds, and can also be represented by a 3D conformation with 3-dimensional coordinates of all atoms. We note that most previous work handles 2D and 3D information separately, while jointly leveraging these two sources may foster a more informative representation. In this work, we explore this appealing idea and propose a new representation learning method based on a unified 2D and 3D pre-training. Atom coordinates and interatomic distances are encoded and then fused with atomic representations through graph neural networks. The model is pre-trained on three tasks: reconstruction of masked atoms and coordinates, 3D conformation generation conditioned on 2D graph, and 2D graph generation conditioned on 3D conformation. We evaluate our method on 11 downstream molecular property prediction tasks: 7 with 2D information only and 4 with both 2D and 3D information. Our method achieves state-of-the-art results on 10 tasks, and the average improvement on 2D-only tasks is 8.3%. Our method also achieves significant improvement on two 3D conformation generation tasks.