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Proteins are fundamental components of biological systems and can be represented through various modalities, including sequences, structures, and textual descriptions. Despite the advances in deep learning and scientific large language models (LLMs) for protein research, current methodologies predominantly focus on limited specialized tasks -- often predicting one protein modality from another. These approaches restrict the understanding and generation of multimodal protein data. In contrast, large multimodal models have demonstrated potential capabilities in generating any-to-any content like text, images, and videos, thus enriching user interactions across various domains. Integrating these multimodal model technologies into protein research offers significant promise by potentially transforming how proteins are studied. To this end, we introduce HelixProtX, a system built upon the large multimodal model, aiming to offer a comprehensive solution to protein research by supporting any-to-any protein modality generation. Unlike existing methods, it allows for the transformation of any input protein modality into any desired protein modality. The experimental results affirm the advanced capabilities of HelixProtX, not only in generating functional descriptions from amino acid sequences but also in executing critical tasks such as designing protein sequences and structures from textual descriptions. Preliminary findings indicate that HelixProtX consistently achieves superior accuracy across a range of protein-related tasks, outperforming existing state-of-the-art models. By integrating multimodal large models into protein research, HelixProtX opens new avenues for understanding protein biology, thereby promising to accelerate scientific discovery.

While monomer protein structure prediction tools boast impressive accuracy, the prediction of protein complex structures remains a daunting challenge in the field. This challenge is particularly pronounced in scenarios involving complexes with protein chains from different species, such as antigen-antibody interactions, where accuracy often falls short. Limited by the accuracy of complex prediction, tasks based on precise protein-protein interaction analysis also face obstacles. In this report, we highlight the ongoing advancements of our protein complex structure prediction model, HelixFold-Multimer, underscoring its enhanced performance. HelixFold-Multimer provides precise predictions for diverse protein complex structures, especially in therapeutic protein interactions. Notably, HelixFold-Multimer achieves remarkable success in antigen-antibody and peptide-protein structure prediction, greatly surpassing AlphaFold 3. HelixFold-Multimer is now available for public use on the PaddleHelix platform, offering both a general version and an antigen-antibody version. Researchers can conveniently access and utilize this service for their development needs.

Protein-ligand structure prediction is an essential task in drug discovery, predicting the binding interactions between small molecules (ligands) and target proteins (receptors). Recent advances have incorporated deep learning techniques to improve the accuracy of protein-ligand structure prediction. Nevertheless, the experimental validation of docking conformations remains costly, it raises concerns regarding the generalizability of these deep learning-based methods due to the limited training data. In this work, we show that by pre-training on a large-scale docking conformation generated by traditional physics-based docking tools and then fine-tuning with a limited set of experimentally validated receptor-ligand complexes, we can obtain a protein-ligand structure prediction model with outstanding performance. Specifically, this process involved the generation of 100 million docking conformations for protein-ligand pairings, an endeavor consuming roughly 1 million CPU core days. The proposed model, HelixDock, aims to acquire the physical knowledge encapsulated by the physics-based docking tools during the pre-training phase. HelixDock has been rigorously benchmarked against both physics-based and deep learning-based baselines, demonstrating its exceptional precision and robust transferability in predicting binding confirmation. In addition, our investigation reveals the scaling laws governing pre-trained protein-ligand structure prediction models, indicating a consistent enhancement in performance with increases in model parameters and the volume of pre-training data. Moreover, we applied HelixDock to several drug discovery-related tasks to validate its practical utility. HelixDock demonstrates outstanding capabilities on both cross-docking and structure-based virtual screening benchmarks.

The accuracy of AlphaFold2, a frontier end-to-end structure prediction system, is already close to that of the experimental determination techniques. Due to the complex model architecture and large memory consumption, it requires lots of computational resources and time to train AlphaFold2 from scratch. Efficient AlphaFold2 training could accelerate the development of life science. In this paper, we propose a Parallel Evoformer and Branch Parallelism to speed up the training of AlphaFold2. We conduct sufficient experiments on UniFold implemented in PyTorch and HelixFold implemented in PaddlePaddle, and Branch Parallelism can improve the training performance by 38.67% and 36.93%, respectively. We also demonstrate that the accuracy of Parallel Evoformer could be on par with AlphaFold2 on the CASP14 and CAMEO datasets. The source code is available on https://github.com/PaddlePaddle/PaddleFleetX, Comment: arXiv admin note: substantial text overlap with arXiv:2207.05477

Estimated time of arrival (ETA) prediction, also known as travel time estimation, is a fundamental task for a wide range of intelligent transportation applications, such as navigation, route planning, and ride-hailing services. To accurately predict the travel time of a route, it is essential to take into account both contextual and predictive factors, such as spatial-temporal interaction, driving behavior, and traffic congestion propagation inference. The ETA prediction models previously deployed at Baidu Maps have addressed the factors of spatial-temporal interaction (ConSTGAT) and driving behavior (SSML). In this work, we focus on modeling traffic congestion propagation patterns to improve ETA performance. Traffic congestion propagation pattern modeling is challenging, and it requires accounting for impact regions over time and cumulative effect of delay variations over time caused by traffic events on the road network. In this paper, we present a practical industrial-grade ETA prediction framework named DuETA. Specifically, we construct a congestion-sensitive graph based on the correlations of traffic patterns, and we develop a route-aware graph transformer to directly learn the long-distance correlations of the road segments. This design enables DuETA to capture the interactions between the road segment pairs that are spatially distant but highly correlated with traffic conditions. Extensive experiments are conducted on large-scale, real-world datasets collected from Baidu Maps. Experimental results show that ETA prediction can significantly benefit from the learned traffic congestion propagation patterns. In addition, DuETA has already been deployed in production at Baidu Maps, serving billions of requests every day. This demonstrates that DuETA is an industrial-grade and robust solution for large-scale ETA prediction services., Comment: To appear at CIKM 2022

Molecular property prediction is a fundamental task in the drug and material industries. Physically, the properties of a molecule are determined by its own electronic structure, which is a quantum many-body system and can be exactly described by the Schr"odinger equation. Full-range many-body interactions between electrons have been proven effective in obtaining an accurate solution of the Schr"odinger equation by classical computational chemistry methods, although modeling such interactions consumes an expensive computational cost. Meanwhile, deep learning methods have also demonstrated their competence in molecular property prediction tasks. Inspired by the classical computational chemistry methods, we design a novel method, namely GEM-2, which comprehensively considers full-range many-body interactions in molecules. Multiple tracks are utilized to model the full-range interactions between the many-bodies with different orders, and a novel axial attention mechanism is designed to approximate the full-range interaction modeling with much lower computational cost. Extensive experiments demonstrate the overwhelming superiority of GEM-2 over multiple baseline methods in quantum chemistry and drug discovery tasks. The ablation studies also verify the effectiveness of the full-range many-body interactions.

AI-based protein structure prediction pipelines, such as AlphaFold2, have achieved near-experimental accuracy. These advanced pipelines mainly rely on Multiple Sequence Alignments (MSAs) as inputs to learn the co-evolution information from the homologous sequences. Nonetheless, searching MSAs from protein databases is time-consuming, usually taking dozens of minutes. Consequently, we attempt to explore the limits of fast protein structure prediction by using only primary sequences of proteins. HelixFold-Single is proposed to combine a large-scale protein language model with the superior geometric learning capability of AlphaFold2. Our proposed method, HelixFold-Single, first pre-trains a large-scale protein language model (PLM) with thousands of millions of primary sequences utilizing the self-supervised learning paradigm, which will be used as an alternative to MSAs for learning the co-evolution information. Then, by combining the pre-trained PLM and the essential components of AlphaFold2, we obtain an end-to-end differentiable model to predict the 3D coordinates of atoms from only the primary sequence. HelixFold-Single is validated in datasets CASP14 and CAMEO, achieving competitive accuracy with the MSA-based methods on the targets with large homologous families. Furthermore, HelixFold-Single consumes much less time than the mainstream pipelines for protein structure prediction, demonstrating its potential in tasks requiring many predictions. The code of HelixFold-Single is available at https://github.com/PaddlePaddle/PaddleHelix/tree/dev/apps/protein_folding/helixfold-single, and we also provide stable web services on https://paddlehelix.baidu.com/app/drug/protein-single/forecast.

Accurate protein structure prediction can significantly accelerate the development of life science. The accuracy of AlphaFold2, a frontier end-to-end structure prediction system, is already close to that of the experimental determination techniques. Due to the complex model architecture and large memory consumption, it requires lots of computational resources and time to implement the training and inference of AlphaFold2 from scratch. The cost of running the original AlphaFold2 is expensive for most individuals and institutions. Therefore, reducing this cost could accelerate the development of life science. We implement AlphaFold2 using PaddlePaddle, namely HelixFold, to improve training and inference speed and reduce memory consumption. The performance is improved by operator fusion, tensor fusion, and hybrid parallelism computation, while the memory is optimized through Recompute, BFloat16, and memory read/write in-place. Compared with the original AlphaFold2 (implemented with Jax) and OpenFold (implemented with PyTorch), HelixFold needs only 7.5 days to complete the full end-to-end training and only 5.3 days when using hybrid parallelism, while both AlphaFold2 and OpenFold take about 11 days. HelixFold saves 1x training time. We verified that HelixFold's accuracy could be on par with AlphaFold2 on the CASP14 and CAMEO datasets. HelixFold's code is available on GitHub for free download: https://github.com/PaddlePaddle/PaddleHelix/tree/dev/apps/protein_folding/helixfold, and we also provide stable web services on https://paddlehelix.baidu.com/app/drug/protein/forecast.

Predicting clinical outcomes to anti-cancer drugs on a personalized basis is challenging in cancer treatment due to the heterogeneity of tumors. Traditional computational efforts have been made to model the effect of drug response on individual samples depicted by their molecular profile, yet overfitting occurs because of the high dimension for omics data, hindering models from clinical application. Recent research shows that deep learning is a promising approach to build drug response models by learning alignment patterns between drugs and samples. However, existing studies employed the simple feature fusion strategy and only considered the drug features as a whole representation while ignoring the substructure information that may play a vital role when aligning drugs and genes. Hereby in this paper, we propose TCR (Transformer based network for Cancer drug Response) to predict anti-cancer drug response. By utilizing an attention mechanism, TCR is able to learn the interactions between drug atom/sub-structure and molecular signatures efficiently in our study. Furthermore, a dual loss function and cross sampling strategy were designed to improve the prediction power of TCR. We show that TCR outperformed all other methods under various data splitting strategies on all evaluation matrices (some with significant improvement). Extensive experiments demonstrate that TCR shows significantly improved generalization ability on independent in-vitro experiments and in-vivo real patient data. Our study highlights the prediction power of TCR and its potential value for cancer drug repurpose and precision oncology treatment., Comment: 11 pages,7 figures

Accurate ADMET (an abbreviation for "absorption, distribution, metabolism, excretion, and toxicity") predictions can efficiently screen out undesirable drug candidates in the early stage of drug discovery. In recent years, multiple comprehensive ADMET systems that adopt advanced machine learning models have been developed, providing services to estimate multiple endpoints. However, those ADMET systems usually suffer from weak extrapolation ability. First, due to the lack of labelled data for each endpoint, typical machine learning models perform frail for the molecules with unobserved scaffolds. Second, most systems only provide fixed built-in endpoints and cannot be customised to satisfy various research requirements. To this end, we develop a robust and endpoint extensible ADMET system, HelixADMET (H-ADMET). H-ADMET incorporates the concept of self-supervised learning to produce a robust pre-trained model. The model is then fine-tuned with a multi-task and multi-stage framework to transfer knowledge between ADMET endpoints, auxiliary tasks, and self-supervised tasks. Our results demonstrate that H-ADMET achieves an overall improvement of 4%, compared with existing ADMET systems on comparable endpoints. Additionally, the pre-trained model provided by H-ADMET can be fine-tuned to generate new and customised ADMET endpoints, meeting various demands of drug research and development requirements.

Protein-protein interactions (PPIs) are essentials for many biological processes where two or more proteins physically bind together to achieve their functions. Modeling PPIs is useful for many biomedical applications, such as vaccine design, antibody therapeutics, and peptide drug discovery. Pre-training a protein model to learn effective representation is critical for PPIs. Most pre-training models for PPIs are sequence-based, which naively adopt the language models used in natural language processing to amino acid sequences. More advanced works utilize the structure-aware pre-training technique, taking advantage of the contact maps of known protein structures. However, neither sequences nor contact maps can fully characterize structures and functions of the proteins, which are closely related to the PPI problem. Inspired by this insight, we propose a multimodal protein pre-training model with three modalities: sequence, structure, and function (S2F). Notably, instead of using contact maps to learn the amino acid-level rigid structures, we encode the structure feature with the topology complex of point clouds of heavy atoms. It allows our model to learn structural information about not only the backbones but also the side chains. Moreover, our model incorporates the knowledge from the functional description of proteins extracted from literature or manual annotations. Our experiments show that the S2F learns protein embeddings that achieve good performances on a variety of PPIs tasks, including cross-species PPI, antibody-antigen affinity prediction, antibody neutralization prediction for SARS-CoV-2, and mutation-driven binding affinity change prediction., Comment: MLCB 2021 Spotlight

Efficient exploration of the chemical space to search the candidate drugs that satisfy various constraints is a fundamental task of drug discovery. Advanced deep generative methods attempt to optimize the molecules in the compact latent space instead of the discrete original space, but the mapping between the original and latent spaces is always kept unchanged during the entire optimization process. The unchanged mapping makes those methods challenging to fast adapt to various optimization scenes and leads to the great demand for assessed molecules (samples) to provide optimization direction, which is a considerable expense for drug discovery. To this end, we design a sample-efficient molecular generative method, HelixMO, which explores the scene-sensitive latent space to promote sample efficiency. The scene-sensitive latent space focuses more on modeling the promising molecules by dynamically adjusting the space mapping by leveraging the correlations between the general and scene-specific characteristics during the optimization process. Extensive experiments demonstrate that HelixMO can achieve competitive performance with only a few assessed samples on four molecular optimization scenes. Ablation studies verify the positive impact of the scene-specific latent space, which is capable of identifying the critical characteristics of the promising molecules. We also deployed HelixMO on the website PaddleHelix (https://paddlehelix.baidu.com/app/drug/drugdesign/forecast) to provide drug design service.

Machine learning shows great potential in virtual screening for drug discovery. Current efforts on accelerating docking-based virtual screening do not consider using existing data of other previously developed targets. To make use of the knowledge of the other targets and take advantage of the existing data, in this work, we apply multi-task learning to the problem of docking-based virtual screening. With two large docking datasets, the results of extensive experiments show that multi-task learning can achieve better performances on docking score prediction. By learning knowledge across multiple targets, the model trained by multi-task learning shows a better ability to adapt to a new target. Additional empirical study shows that other problems in drug discovery, such as the experimental drug-target affinity prediction, may also benefit from multi-task learning. Our results demonstrate that multi-task learning is a promising machine learning approach for docking-based virtual screening and accelerating the process of drug discovery., Comment: accepted by IEEE International Conference on Bioinformatics and Biomedicine (BIBM 2021)

In this report, we (SuperHelix team) present our solution to KDD Cup 2021-PCQM4M-LSC, a large-scale quantum chemistry dataset on predicting HOMO-LUMO gap of molecules. Our solution, Lite Geometry Enhanced Molecular representation learning (LiteGEM) achieves a mean absolute error (MAE) of 0.1204 on the test set with the help of deep graph neural networks and various self-supervised learning tasks. The code of the framework can be found in https://github.com/PaddlePaddle/PaddleHelix/tree/dev/competition/kddcup2021-PCQM4M-LSC/.

Effective molecular representation learning is of great importance to facilitate molecular property prediction, which is a fundamental task for the drug and material industry. Recent advances in graph neural networks (GNNs) have shown great promise in applying GNNs for molecular representation learning. Moreover, a few recent studies have also demonstrated successful applications of self-supervised learning methods to pre-train the GNNs to overcome the problem of insufficient labeled molecules. However, existing GNNs and pre-training strategies usually treat molecules as topological graph data without fully utilizing the molecular geometry information. Whereas, the three-dimensional (3D) spatial structure of a molecule, a.k.a molecular geometry, is one of the most critical factors for determining molecular physical, chemical, and biological properties. To this end, we propose a novel Geometry Enhanced Molecular representation learning method (GEM) for Chemical Representation Learning (ChemRL). At first, we design a geometry-based GNN architecture that simultaneously models atoms, bonds, and bond angles in a molecule. To be specific, we devised double graphs for a molecule: The first one encodes the atom-bond relations; The second one encodes bond-angle relations. Moreover, on top of the devised GNN architecture, we propose several novel geometry-level self-supervised learning strategies to learn spatial knowledge by utilizing the local and global molecular 3D structures. We compare ChemRL-GEM with various state-of-the-art (SOTA) baselines on different molecular benchmarks and exhibit that ChemRL-GEM can significantly outperform all baselines in both regression and classification tasks. For example, the experimental results show an overall improvement of 8.8% on average compared to SOTA baselines on the regression tasks, demonstrating the superiority of the proposed method., Comment: Nature Machine Intelligence, 2022

In recommender systems such as news feed stream, it is essential to optimize the long-term utilities in the continuous user-system interaction processes. Previous works have proved the capability of reinforcement learning in this problem. However, there are many practical challenges to implement deep reinforcement learning in online systems, including low sample efficiency, uncontrollable risks, and excessive variances. To address these issues, we propose a novel reinforcement learning method, namely model-based counterfactual advantage learning (MBCAL). The proposed method takes advantage of the characteristics of recommender systems and draws ideas from the model-based reinforcement learning method for higher sample efficiency. It has two components: an environment model that predicts the instant user behavior one-by-one in an auto-regressive form, and a future advantage model that predicts the future utility. To alleviate the impact of excessive variance when learning the future advantage model, we employ counterfactual comparisons derived from the environment model. In consequence, the proposed method possesses high sample efficiency and significantly lower variance; Also, it is able to use existing user logs to avoid the risks of starting from scratch. In contrast to its capability, its implementation cost is relatively low, which fits well with practical systems. Theoretical analysis and elaborate experiments are presented. Results show that the proposed method transcends the other supervised learning and RL-based methods in both sample efficiency and asymptotic performances.

In the combinatorial recommender systems, multiple items are fed to the user at one time in the result page, where the correlations among the items have impact on the user behavior. In this work, we model the combinatorial recommendation as the problem of generating a sequence(ordered list) of items from a candidate set, with the target of maximizing the expected overall utility(e.g. total clicks) of the sequence. Toward solving this problem, we propose the Evaluation-Generation framework. On the one hand of this framework, an evaluation model is trained to evaluate the expected overall utility, by fully considering the user, item information and the correlations among the co-exposed items. On the other hand, generation policies based on heuristic searching or reinforcement learning are devised to generate potential high-quality sequences, from which the evaluation model select one to expose. We propose effective model architectures and learning metrics under this framework. We also offer series of offline tests to thoroughly investigate the performance of the proposed framework, as supplements to the online experiments. Our results show obvious increase in performance compared with the previous solutions.

Aerators are essential and crucial auxiliary devices in intensive culture, especially in industrial culture in China. The traditional methods cannot accurately detect abnormal condition of aerators in time. Surveillance cameras are widely used as visual perception modules of the Internet of Things, and then using these widely existing surveillance cameras to realize real-time anomaly detection of aerators is a cost-free and easy-to-promote method. However, it is difficult to develop such an expert system due to some technical and applied challenges, e.g., illumination, occlusion, complex background, etc. To tackle these aforementioned challenges, we propose a real-time expert system based on computer vision technology and existing surveillance cameras for anomaly detection of aerators, which consists of two modules, i.e., object region detection and working state detection. First, it is difficult to detect the working state for some small object regions in whole images, and the time complexity of global feature comparison is also high, so we present an object region detection method based on the region proposal idea. Moreover, we propose a novel algorithm called reference frame Kanade-Lucas-Tomasi (RF-KLT) algorithm for motion feature extraction in fixed regions. Then, we present a dimension reduction method of time series for establishing a feature dataset with obvious boundaries between classes. Finally, we use machine learning algorithms to build the feature classifier. The experimental results in both the actual video dataset and the augmented video dataset show that the accuracy for detecting object region and working state of aerators is 100% and 99.9% respectively, and the detection speed is 77-333 frames per second (FPS) according to the different types of surveillance cameras., Comment: 17 figures