Multi-task Bioassay Pre-training for Protein-ligand Binding Affinity Prediction

Protein-ligand binding affinity (PLBA) prediction is the fundamental task in drug discovery. Recently, various deep learning-based models predict binding affinity by incorporating the three-dimensional structure of protein-ligand complexes as input and achieving astounding progress. However, due to the scarcity of high-quality training data, the generalization ability of current models is still limited. In addition, different bioassays use varying affinity measurement labels (i.e., IC50, Ki, Kd), and different experimental conditions inevitably introduce systematic noise, which poses a significant challenge to constructing high-precision affinity prediction models. To address these issues, we (1) propose Multi-task Bioassay Pre-training (MBP), a pre-training framework for structure-based PLBA prediction; (2) construct a pre-training dataset called ChEMBL-Dock with more than 300k experimentally measured affinity labels and about 2.8M docked three-dimensional structures. By introducing multi-task pre-training to treat the prediction of different affinity labels as different tasks and classifying relative rankings between samples from the same bioassay, MBP learns robust and transferrable structural knowledge from our new ChEMBL-Dock dataset with varied and noisy labels. Experiments substantiate the capability of MBP as a general framework that can improve and be tailored to mainstream structure-based PLBA prediction tasks. To the best of our knowledge, MBP is the first affinity pre-training model and shows great potential for future development.

Multi-Constraint Molecular Generation using Sparsely Labelled Training Data for Localized High-Concentration Electrolyte Diluent Screening

Recently, machine learning methods have been used to propose molecules with desired properties, which is especially useful for exploring large chemical spaces efficiently. However, these methods rely on fully labelled training data, and are not practical in situations where molecules with multiple property constraints are required. There is often insufficient training data for all those properties from publicly available databases, especially when ab-initio simulation or experimental property data is also desired for training the conditional molecular generative model. In this work, we show how to modify a semi-supervised variational auto-encoder (SSVAE) model which only works with fully labelled and fully unlabelled molecular property training data into the ConGen model, which also works on training data that have sparsely populated labels. We evaluate ConGen's performance in generating molecules with multiple constraints when trained on a dataset combined from multiple publicly available molecule property databases, and demonstrate an example application of building the virtual chemical space for potential Lithium-ion battery localized high-concentration electrolyte (LHCE) diluents.

Protein-Ligand Complex Generator & Drug Screening via Tiered Tensor Transform

Accurate determination of a small molecule candidate (ligand) binding pose in its target protein pocket is important for computer-aided drug discovery. Typical rigid-body docking methods ignore the pocket flexibility of protein, while the more accurate pose generation using molecular dynamics is hindered by slow protein dynamics. We develop a tiered tensor transform (3T) algorithm to rapidly generate diverse protein-ligand complex conformations for both pose and affinity estimation in drug screening, requiring neither machine learning training nor lengthy dynamics computation, while maintaining both coarse-grain-like coordinated protein dynamics and atomistic-level details of the complex pocket. The 3T conformation structures we generate are closer to experimental co-crystal structures than those generated by docking software, and more importantly achieve significantly higher accuracy in active ligand classification than traditional ensemble docking using hundreds of experimental protein conformations. 3T structure transformation is decoupled from the system physics, making future usage in other computational scientific domains possible.

Spatio-Temporal Contrastive Learning Enhanced GNNs for Session-based Recommendation

Session-based recommendation (SBR) systems aim to utilize the user's short-term behavior sequence to predict the next item without the detailed user profile. Most recent works try to model the user preference by treating the sessions as between-item transition graphs and utilize various graph neural networks (GNNs) to encode the representations of pair-wise relations among items and their neighbors. Some of the existing GNN-based models mainly focus on aggregating information from the view of spatial graph structure, which ignores the temporal relations within neighbors of an item during message passing and the information loss results in a sub-optimal problem. Other works embrace this challenge by incorporating additional temporal information but lack sufficient interaction between the spatial and temporal patterns. To address this issue, inspired by the uniformity and alignment properties of contrastive learning techniques, we propose a novel framework called Session-based Recommendation with Spatio-Temporal Contrastive Learning Enhanced GNNs (RESTC). The idea is to supplement the GNN-based main supervised recommendation task with the temporal representation via an auxiliary cross-view contrastive learning mechanism. Furthermore, a novel global collaborative filtering graph (CFG) embedding is leveraged to enhance the spatial view in the main task. Extensive experiments demonstrate the significant performance of RESTC compared with the state-of-the-art baselines e.g., with an improvement as much as 27.08% gain on HR@20 and 20.10% gain on MRR@20.

Mask and Reason: Pre-Training Knowledge Graph Transformers for Complex Logical Queries

Knowledge graph (KG) embeddings have been a mainstream approach for reasoning over incomplete KGs. However, limited by their inherently shallow and static architectures, they can hardly deal with the rising focus on complex logical queries, which comprise logical operators, imputed edges, multiple source entities, and unknown intermediate entities. In this work, we present the Knowledge Graph Transformer (kgTransformer) with masked pre-training and fine-tuning strategies. We design a KG triple transformation method to enable Transformer to handle KGs, which is further strengthened by the Mixture-of-Experts (MoE) sparse activation. We then formulate the complex logical queries as masked prediction and introduce a two-stage masked pre-training strategy to improve transferability and generalizability. Extensive experiments on two benchmarks demonstrate that kgTransformer can consistently outperform both KG embedding-based baselines and advanced encoders on nine in-domain and out-of-domain reasoning tasks. Additionally, kgTransformer can reason with explainability via providing the full reasoning paths to interpret given answers.

Learning Large-scale Network Embedding from Representative Subgraph

We study the problem of large-scale network embedding, which aims to learn low-dimensional latent representations for network mining applications. Recent research in the field of network embedding has led to significant progress such as DeepWalk, LINE, NetMF, NetSMF. However, the huge size of many real-world networks makes it computationally expensive to learn network embedding from the entire network. In this work, we present a novel network embedding method called "NES", which learns network embedding from a small representative subgraph. NES leverages theories from graph sampling to efficiently construct representative subgraph with smaller size which can be used to make inferences about the full network, enabling significantly improved efficiency in embedding learning. Then, NES computes the network embedding from this representative subgraph, efficiently. Compared with well-known methods, extensive experiments on networks of various scales and types demonstrate that NES achieves comparable performance and significant efficiency superiority.

Stable Prediction on Graphs with Agnostic Distribution Shift

Graph is a flexible and effective tool to represent complex structures in practice and graph neural networks (GNNs) have been shown to be effective on various graph tasks with randomly separated training and testing data. In real applications, however, the distribution of training graph might be different from that of the test one (e.g., users' interactions on the user-item training graph and their actual preference on items, i.e., testing environment, are known to have inconsistencies in recommender systems). Moreover, the distribution of test data is always agnostic when GNNs are trained. Hence, we are facing the agnostic distribution shift between training and testing on graph learning, which would lead to unstable inference of traditional GNNs across different test environments. To address this problem, we propose a novel stable prediction framework for GNNs, which permits both locally and globally stable learning and prediction on graphs. In particular, since each node is partially represented by its neighbors in GNNs, we propose to capture the stable properties for each node (locally stable) by re-weighting the information propagation/aggregation processes. For global stability, we propose a stable regularizer that reduces the training losses on heterogeneous environments and thus warping the GNNs to generalize well. We conduct extensive experiments on several graph benchmarks and a noisy industrial recommendation dataset that is collected from 5 consecutive days during a product promotion festival. The results demonstrate that our method outperforms various SOTA GNNs for stable prediction on graphs with agnostic distribution shift, including shift caused by node labels and attributes.

Fast Extraction of Word Embedding from Q-contexts

The notion of word embedding plays a fundamental role in natural language processing (NLP). However, pre-training word embedding for very large-scale vocabulary is computationally challenging for most existing methods. In this work, we show that with merely a small fraction of contexts (Q-contexts)which are typical in the whole corpus (and their mutual information with words), one can construct high-quality word embedding with negligible errors. Mutual information between contexts and words can be encoded canonically as a sampling state, thus, Q-contexts can be fast constructed. Furthermore, we present an efficient and effective WEQ method, which is capable of extracting word embedding directly from these typical contexts. In practical scenarios, our algorithm runs 11$\sim$13 times faster than well-established methods. By comparing with well-known methods such as matrix factorization, word2vec, GloVeand fasttext, we demonstrate that our method achieves comparable performance on a variety of downstream NLP tasks, and in the meanwhile maintains run-time and resource advantages over all these baselines.

Modeling Protein Using Large-scale Pretrain Language Model

Protein is linked to almost every life process. Therefore, analyzing the biological structure and property of protein sequences is critical to the exploration of life, as well as disease detection and drug discovery. Traditional protein analysis methods tend to be labor-intensive and time-consuming. The emergence of deep learning models makes modeling data patterns in large quantities of data possible. Interdisciplinary researchers have begun to leverage deep learning methods to model large biological datasets, e.g. using long short-term memory and convolutional neural network for protein sequence classification. After millions of years of evolution, evolutionary information is encoded in protein sequences. Inspired by the similarity between natural language and protein sequences, we use large-scale language models to model evolutionary-scale protein sequences, encoding protein biology information in representation. Significant improvements are observed in both token-level and sequence-level tasks, demonstrating that our large-scale model can accurately capture evolution information from pretraining on evolutionary-scale individual sequences. Our code and model are available at https://github.com/THUDM/ProteinLM.

Pre-Trained Models: Past, Present and Future

Large-scale pre-trained models (PTMs) such as BERT and GPT have recently achieved great success and become a milestone in the field of artificial intelligence (AI). Owing to sophisticated pre-training objectives and huge model parameters, large-scale PTMs can effectively capture knowledge from massive labeled and unlabeled data. By storing knowledge into huge parameters and fine-tuning on specific tasks, the rich knowledge implicitly encoded in huge parameters can benefit a variety of downstream tasks, which has been extensively demonstrated via experimental verification and empirical analysis. It is now the consensus of the AI community to adopt PTMs as backbone for downstream tasks rather than learning models from scratch. In this paper, we take a deep look into the history of pre-training, especially its special relation with transfer learning and self-supervised learning, to reveal the crucial position of PTMs in the AI development spectrum. Further, we comprehensively review the latest breakthroughs of PTMs. These breakthroughs are driven by the surge of computational power and the increasing availability of data, towards four important directions: designing effective architectures, utilizing rich contexts, improving computational efficiency, and conducting interpretation and theoretical analysis. Finally, we discuss a series of open problems and research directions of PTMs, and hope our view can inspire and advance the future study of PTMs.