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Deep Lead Optimization: Leveraging Generative AI for Structural Modification
Apr 30, 2024
The idea of using deep-learning-based molecular generation to accelerate discovery of drug candidates has attracted extraordinary attention, and many deep generative models have been developed for automated drug design, termed molecular generation. In general, molecular generation encompasses two main strategies: de novo design, which generates novel molecular structures from scratch, and lead optimization, which refines existing molecules into drug candidates. Among them, lead optimization plays an important role in real-world drug design. For example, it can enable the development of me-better drugs that are chemically distinct yet more effective than the original drugs. It can also facilitate fragment-based drug design, transforming virtual-screened small ligands with low affinity into first-in-class medicines. Despite its importance, automated lead optimization remains underexplored compared to the well-established de novo generative models, due to its reliance on complex biological and chemical knowledge. To bridge this gap, we conduct a systematic review of traditional computational methods for lead optimization, organizing these strategies into four principal sub-tasks with defined inputs and outputs. This review delves into the basic concepts, goals, conventional CADD techniques, and recent advancements in AIDD. Additionally, we introduce a unified perspective based on constrained subgraph generation to harmonize the methodologies of de novo design and lead optimization. Through this lens, de novo design can incorporate strategies from lead optimization to address the challenge of generating hard-to-synthesize molecules; inversely, lead optimization can benefit from the innovations in de novo design by approaching it as a task of generating molecules conditioned on certain substructures.
LongVQ: Long Sequence Modeling with Vector Quantization on Structured Memory
Apr 18, 2024
Transformer models have been successful in various sequence processing tasks, but the self-attention mechanism's computational cost limits its practicality for long sequences. Although there are existing attention variants that improve computational efficiency, they have a limited ability to abstract global information effectively based on their hand-crafted mixing strategies. On the other hand, state-space models (SSMs) are tailored for long sequences but cannot capture complicated local information. Therefore, the combination of them as a unified token mixer is a trend in recent long-sequence models. However, the linearized attention degrades performance significantly even when equipped with SSMs. To address the issue, we propose a new method called LongVQ. LongVQ uses the vector quantization (VQ) technique to compress the global abstraction as a length-fixed codebook, enabling the linear-time computation of the attention matrix. This technique effectively maintains dynamic global and local patterns, which helps to complement the lack of long-range dependency issues. Our experiments on the Long Range Arena benchmark, autoregressive language modeling, and image and speech classification demonstrate the effectiveness of LongVQ. Our model achieves significant improvements over other sequence models, including variants of Transformers, Convolutions, and recent State Space Models.
A Teacher-Free Graph Knowledge Distillation Framework with Dual Self-Distillation
Mar 06, 2024
Recent years have witnessed great success in handling graph-related tasks with Graph Neural Networks (GNNs). Despite their great academic success, Multi-Layer Perceptrons (MLPs) remain the primary workhorse for practical industrial applications. One reason for such an academic-industry gap is the neighborhood-fetching latency incurred by data dependency in GNNs. To reduce their gaps, Graph Knowledge Distillation (GKD) is proposed, usually based on a standard teacher-student architecture, to distill knowledge from a large teacher GNN into a lightweight student GNN or MLP. However, we found in this paper that neither teachers nor GNNs are necessary for graph knowledge distillation. We propose a Teacher-Free Graph Self-Distillation (TGS) framework that does not require any teacher model or GNNs during both training and inference. More importantly, the proposed TGS framework is purely based on MLPs, where structural information is only implicitly used to guide dual knowledge self-distillation between the target node and its neighborhood. As a result, TGS enjoys the benefits of graph topology awareness in training but is free from data dependency in inference. Extensive experiments have shown that the performance of vanilla MLPs can be greatly improved with dual self-distillation, e.g., TGS improves over vanilla MLPs by 15.54% on average and outperforms state-of-the-art GKD algorithms on six real-world datasets. In terms of inference speed, TGS infers 75X-89X faster than existing GNNs and 16X-25X faster than classical inference acceleration methods.
Decoupling Weighing and Selecting for Integrating Multiple Graph Pre-training Tasks
Mar 03, 2024
Recent years have witnessed the great success of graph pre-training for graph representation learning. With hundreds of graph pre-training tasks proposed, integrating knowledge acquired from multiple pre-training tasks has become a popular research topic. In this paper, we identify two important collaborative processes for this topic: (1) select: how to select an optimal task combination from a given task pool based on their compatibility, and (2) weigh: how to weigh the selected tasks based on their importance. While there currently has been a lot of work focused on weighing, comparatively little effort has been devoted to selecting. This paper proposes a novel instance-level framework for integrating multiple graph pre-training tasks, Weigh And Select (WAS), where the two collaborative processes, weighing and selecting, are combined by decoupled siamese networks. Specifically, it first adaptively learns an optimal combination of tasks for each instance from a given task pool, based on which a customized instance-level task weighing strategy is learned. Extensive experiments on 16 graph datasets across node-level and graph-level downstream tasks have demonstrated that by combining a few simple but classical tasks, WAS can achieve comparable performance to other leading counterparts. The code is available at https://github.com/TianyuFan0504/WAS.
Enhancing Protein Predictive Models via Proteins Data Augmentation: A Benchmark and New Directions
Mar 01, 2024
Augmentation is an effective alternative to utilize the small amount of labeled protein data. However, most of the existing work focuses on design-ing new architectures or pre-training tasks, and relatively little work has studied data augmentation for proteins. This paper extends data augmentation techniques previously used for images and texts to proteins and then benchmarks these techniques on a variety of protein-related tasks, providing the first comprehensive evaluation of protein augmentation. Furthermore, we propose two novel semantic-level protein augmentation methods, namely Integrated Gradients Substitution and Back Translation Substitution, which enable protein semantic-aware augmentation through saliency detection and biological knowledge. Finally, we integrate extended and proposed augmentations into an augmentation pool and propose a simple but effective framework, namely Automated Protein Augmentation (APA), which can adaptively select the most suitable augmentation combinations for different tasks. Extensive experiments have shown that APA enhances the performance of five protein related tasks by an average of 10.55% across three architectures compared to vanilla implementations without augmentation, highlighting its potential to make a great impact on the field.
MAPE-PPI: Towards Effective and Efficient Protein-Protein Interaction Prediction via Microenvironment-Aware Protein Embedding
Feb 22, 2024Protein-Protein Interactions (PPIs) are fundamental in various biological processes and play a key role in life activities. The growing demand and cost of experimental PPI assays require computational methods for efficient PPI prediction. While existing methods rely heavily on protein sequence for PPI prediction, it is the protein structure that is the key to determine the interactions. To take both protein modalities into account, we define the microenvironment of an amino acid residue by its sequence and structural contexts, which describe the surrounding chemical properties and geometric features. In addition, microenvironments defined in previous work are largely based on experimentally assayed physicochemical properties, for which the "vocabulary" is usually extremely small. This makes it difficult to cover the diversity and complexity of microenvironments. In this paper, we propose Microenvironment-Aware Protein Embedding for PPI prediction (MPAE-PPI), which encodes microenvironments into chemically meaningful discrete codes via a sufficiently large microenvironment "vocabulary" (i.e., codebook). Moreover, we propose a novel pre-training strategy, namely Masked Codebook Modeling (MCM), to capture the dependencies between different microenvironments by randomly masking the codebook and reconstructing the input. With the learned microenvironment codebook, we can reuse it as an off-the-shelf tool to efficiently and effectively encode proteins of different sizes and functions for large-scale PPI prediction. Extensive experiments show that MAPE-PPI can scale to PPI prediction with millions of PPIs with superior trade-offs between effectiveness and computational efficiency than the state-of-the-art competitors.
Re-Dock: Towards Flexible and Realistic Molecular Docking with Diffusion Bridge
Feb 21, 2024Accurate prediction of protein-ligand binding structures, a task known as molecular docking is crucial for drug design but remains challenging. While deep learning has shown promise, existing methods often depend on holo-protein structures (docked, and not accessible in realistic tasks) or neglect pocket sidechain conformations, leading to limited practical utility and unrealistic conformation predictions. To fill these gaps, we introduce an under-explored task, named flexible docking to predict poses of ligand and pocket sidechains simultaneously and introduce Re-Dock, a novel diffusion bridge generative model extended to geometric manifolds. Specifically, we propose energy-to-geometry mapping inspired by the Newton-Euler equation to co-model the binding energy and conformations for reflecting the energy-constrained docking generative process. Comprehensive experiments on designed benchmark datasets including apo-dock and cross-dock demonstrate our model's superior effectiveness and efficiency over current methods.
PSC-CPI: Multi-Scale Protein Sequence-Structure Contrasting for Efficient and Generalizable Compound-Protein Interaction Prediction
Feb 13, 2024Compound-Protein Interaction (CPI) prediction aims to predict the pattern and strength of compound-protein interactions for rational drug discovery. Existing deep learning-based methods utilize only the single modality of protein sequences or structures and lack the co-modeling of the joint distribution of the two modalities, which may lead to significant performance drops in complex real-world scenarios due to various factors, e.g., modality missing and domain shifting. More importantly, these methods only model protein sequences and structures at a single fixed scale, neglecting more fine-grained multi-scale information, such as those embedded in key protein fragments. In this paper, we propose a novel multi-scale Protein Sequence-structure Contrasting framework for CPI prediction (PSC-CPI), which captures the dependencies between protein sequences and structures through both intra-modality and cross-modality contrasting. We further apply length-variable protein augmentation to allow contrasting to be performed at different scales, from the amino acid level to the sequence level. Finally, in order to more fairly evaluate the model generalizability, we split the test data into four settings based on whether compounds and proteins have been observed during the training stage. Extensive experiments have shown that PSC-CPI generalizes well in all four settings, particularly in the more challenging ``Unseen-Both" setting, where neither compounds nor proteins have been observed during training. Furthermore, even when encountering a situation of modality missing, i.e., inference with only single-modality protein data, PSC-CPI still exhibits comparable or even better performance than previous approaches.
Protein 3D Graph Structure Learning for Robust Structure-based Protein Property Prediction
Oct 19, 2023
Protein structure-based property prediction has emerged as a promising approach for various biological tasks, such as protein function prediction and sub-cellular location estimation. The existing methods highly rely on experimental protein structure data and fail in scenarios where these data are unavailable. Predicted protein structures from AI tools (e.g., AlphaFold2) were utilized as alternatives. However, we observed that current practices, which simply employ accurately predicted structures during inference, suffer from notable degradation in prediction accuracy. While similar phenomena have been extensively studied in general fields (e.g., Computer Vision) as model robustness, their impact on protein property prediction remains unexplored. In this paper, we first investigate the reason behind the performance decrease when utilizing predicted structures, attributing it to the structure embedding bias from the perspective of structure representation learning. To study this problem, we identify a Protein 3D Graph Structure Learning Problem for Robust Protein Property Prediction (PGSL-RP3), collect benchmark datasets, and present a protein Structure embedding Alignment Optimization framework (SAO) to mitigate the problem of structure embedding bias between the predicted and experimental protein structures. Extensive experiments have shown that our framework is model-agnostic and effective in improving the property prediction of both predicted structures and experimental structures. The benchmark datasets and codes will be released to benefit the community.
WALL-E: Embodied Robotic WAiter Load Lifting with Large Language Model
Aug 31, 2023
Enabling robots to understand language instructions and react accordingly to visual perception has been a long-standing goal in the robotics research community. Achieving this goal requires cutting-edge advances in natural language processing, computer vision, and robotics engineering. Thus, this paper mainly investigates the potential of integrating the most recent Large Language Models (LLMs) and existing visual grounding and robotic grasping system to enhance the effectiveness of the human-robot interaction. We introduce the WALL-E (Embodied Robotic WAiter load lifting with Large Language model) as an example of this integration. The system utilizes the LLM of ChatGPT to summarize the preference object of the users as a target instruction via the multi-round interactive dialogue. The target instruction is then forwarded to a visual grounding system for object pose and size estimation, following which the robot grasps the object accordingly. We deploy this LLM-empowered system on the physical robot to provide a more user-friendly interface for the instruction-guided grasping task. The further experimental results on various real-world scenarios demonstrated the feasibility and efficacy of our proposed framework. See the project website at: https://star-uu-wang.github.io/WALL-E/