Bridge-IF: Learning Inverse Protein Folding with Markov Bridges

Inverse protein folding is a fundamental task in computational protein design, which aims to design protein sequences that fold into the desired backbone structures. While the development of machine learning algorithms for this task has seen significant success, the prevailing approaches, which predominantly employ a discriminative formulation, frequently encounter the error accumulation issue and often fail to capture the extensive variety of plausible sequences. To fill these gaps, we propose Bridge-IF, a generative diffusion bridge model for inverse folding, which is designed to learn the probabilistic dependency between the distributions of backbone structures and protein sequences. Specifically, we harness an expressive structure encoder to propose a discrete, informative prior derived from structures, and establish a Markov bridge to connect this prior with native sequences. During the inference stage, Bridge-IF progressively refines the prior sequence, culminating in a more plausible design. Moreover, we introduce a reparameterization perspective on Markov bridge models, from which we derive a simplified loss function that facilitates more effective training. We also modulate protein language models (PLMs) with structural conditions to precisely approximate the Markov bridge process, thereby significantly enhancing generation performance while maintaining parameter-efficient training. Extensive experiments on well-established benchmarks demonstrate that Bridge-IF predominantly surpasses existing baselines in sequence recovery and excels in the design of plausible proteins with high foldability. The code is available at https://github.com/violet-sto/Bridge-IF.

Structure-Enhanced Protein Instruction Tuning: Towards General-Purpose Protein Understanding

Proteins, as essential biomolecules, play a central role in biological processes, including metabolic reactions and DNA replication. Accurate prediction of their properties and functions is crucial in biological applications. Recent development of protein language models (pLMs) with supervised fine tuning provides a promising solution to this problem. However, the fine-tuned model is tailored for particular downstream prediction task, and achieving general-purpose protein understanding remains a challenge. In this paper, we introduce Structure-Enhanced Protein Instruction Tuning (SEPIT) framework to bridge this gap. Our approach integrates a noval structure-aware module into pLMs to inform them with structural knowledge, and then connects these enhanced pLMs to large language models (LLMs) to generate understanding of proteins. In this framework, we propose a novel two-stage instruction tuning pipeline that first establishes a basic understanding of proteins through caption-based instructions and then refines this understanding using a mixture of experts (MoEs) to learn more complex properties and functional information with the same amount of activated parameters. Moreover, we construct the largest and most comprehensive protein instruction dataset to date, which allows us to train and evaluate the general-purpose protein understanding model. Extensive experimental results on open-ended generation and closed-set answer tasks demonstrate the superior performance of SEPIT over both closed-source general LLMs and open-source LLMs trained with protein knowledge.

Multi-Modal CLIP-Informed Protein Editing

Proteins govern most biological functions essential for life, but achieving controllable protein discovery and optimization remains challenging. Recently, machine learning-assisted protein editing (MLPE) has shown promise in accelerating optimization cycles and reducing experimental workloads. However, current methods struggle with the vast combinatorial space of potential protein edits and cannot explicitly conduct protein editing using biotext instructions, limiting their interactivity with human feedback. To fill these gaps, we propose a novel method called ProtET for efficient CLIP-informed protein editing through multi-modality learning. Our approach comprises two stages: in the pretraining stage, contrastive learning aligns protein-biotext representations encoded by two large language models (LLMs), respectively. Subsequently, during the protein editing stage, the fused features from editing instruction texts and original protein sequences serve as the final editing condition for generating target protein sequences. Comprehensive experiments demonstrated the superiority of ProtET in editing proteins to enhance human-expected functionality across multiple attribute domains, including enzyme catalytic activity, protein stability and antibody specific binding ability. And ProtET improves the state-of-the-art results by a large margin, leading to significant stability improvements of 16.67% and 16.90%. This capability positions ProtET to advance real-world artificial protein editing, potentially addressing unmet academic, industrial, and clinical needs.

Dr3: Ask Large Language Models Not to Give Off-Topic Answers in Open Domain Multi-Hop Question Answering

Open Domain Multi-Hop Question Answering (ODMHQA) plays a crucial role in Natural Language Processing (NLP) by aiming to answer complex questions through multi-step reasoning over retrieved information from external knowledge sources. Recently, Large Language Models (LLMs) have demonstrated remarkable performance in solving ODMHQA owing to their capabilities including planning, reasoning, and utilizing tools. However, LLMs may generate off-topic answers when attempting to solve ODMHQA, namely the generated answers are irrelevant to the original questions. This issue of off-topic answers accounts for approximately one-third of incorrect answers, yet remains underexplored despite its significance. To alleviate this issue, we propose the Discriminate->Re-Compose->Re- Solve->Re-Decompose (Dr3) mechanism. Specifically, the Discriminator leverages the intrinsic capabilities of LLMs to judge whether the generated answers are off-topic. In cases where an off-topic answer is detected, the Corrector performs step-wise revisions along the reversed reasoning chain (Re-Compose->Re-Solve->Re-Decompose) until the final answer becomes on-topic. Experimental results on the HotpotQA and 2WikiMultiHopQA datasets demonstrate that our Dr3 mechanism considerably reduces the occurrence of off-topic answers in ODMHQA by nearly 13%, improving the performance in Exact Match (EM) by nearly 3% compared to the baseline method without the Dr3 mechanism.

Making Pre-trained Language Models Great on Tabular Prediction

The transferability of deep neural networks (DNNs) has made significant progress in image and language processing. However, due to the heterogeneity among tables, such DNN bonus is still far from being well exploited on tabular data prediction (e.g., regression or classification tasks). Condensing knowledge from diverse domains, language models (LMs) possess the capability to comprehend feature names from various tables, potentially serving as versatile learners in transferring knowledge across distinct tables and diverse prediction tasks, but their discrete text representation space is inherently incompatible with numerical feature values in tables. In this paper, we present TP-BERTa, a specifically pre-trained LM for tabular data prediction. Concretely, a novel relative magnitude tokenization converts scalar numerical feature values to finely discrete, high-dimensional tokens, and an intra-feature attention approach integrates feature values with the corresponding feature names. Comprehensive experiments demonstrate that our pre-trained TP-BERTa leads the performance among tabular DNNs and is competitive with Gradient Boosted Decision Tree models in typical tabular data regime.

Generative AI for Controllable Protein Sequence Design: A Survey

The design of novel protein sequences with targeted functionalities underpins a central theme in protein engineering, impacting diverse fields such as drug discovery and enzymatic engineering. However, navigating this vast combinatorial search space remains a severe challenge due to time and financial constraints. This scenario is rapidly evolving as the transformative advancements in AI, particularly in the realm of generative models and optimization algorithms, have been propelling the protein design field towards an unprecedented revolution. In this survey, we systematically review recent advances in generative AI for controllable protein sequence design. To set the stage, we first outline the foundational tasks in protein sequence design in terms of the constraints involved and present key generative models and optimization algorithms. We then offer in-depth reviews of each design task and discuss the pertinent applications. Finally, we identify the unresolved challenges and highlight research opportunities that merit deeper exploration.

GCL: Gradient-Guided Contrastive Learning for Medical Image Segmentation with Multi-Perspective Meta Labels

Since annotating medical images for segmentation tasks commonly incurs expensive costs, it is highly desirable to design an annotation-efficient method to alleviate the annotation burden. Recently, contrastive learning has exhibited a great potential in learning robust representations to boost downstream tasks with limited labels. In medical imaging scenarios, ready-made meta labels (i.e., specific attribute information of medical images) inherently reveal semantic relationships among images, which have been used to define positive pairs in previous work. However, the multi-perspective semantics revealed by various meta labels are usually incompatible and can incur intractable "semantic contradiction" when combining different meta labels. In this paper, we tackle the issue of "semantic contradiction" in a gradient-guided manner using our proposed Gradient Mitigator method, which systematically unifies multi-perspective meta labels to enable a pre-trained model to attain a better high-level semantic recognition ability. Moreover, we emphasize that the fine-grained discrimination ability is vital for segmentation-oriented pre-training, and develop a novel method called Gradient Filter to dynamically screen pixel pairs with the most discriminating power based on the magnitude of gradients. Comprehensive experiments on four medical image segmentation datasets verify that our new method GCL: (1) learns informative image representations and considerably boosts segmentation performance with limited labels, and (2) shows promising generalizability on out-of-distribution datasets.

MolHF: A Hierarchical Normalizing Flow for Molecular Graph Generation

Molecular de novo design is a critical yet challenging task in scientific fields, aiming to design novel molecular structures with desired property profiles. Significant progress has been made by resorting to generative models for graphs. However, limited attention is paid to hierarchical generative models, which can exploit the inherent hierarchical structure (with rich semantic information) of the molecular graphs and generate complex molecules of larger size that we shall demonstrate to be difficult for most existing models. The primary challenge to hierarchical generation is the non-differentiable issue caused by the generation of intermediate discrete coarsened graph structures. To sidestep this issue, we cast the tricky hierarchical generation problem over discrete spaces as the reverse process of hierarchical representation learning and propose MolHF, a new hierarchical flow-based model that generates molecular graphs in a coarse-to-fine manner. Specifically, MolHF first generates bonds through a multi-scale architecture, then generates atoms based on the coarsened graph structure at each scale. We demonstrate that MolHF achieves state-of-the-art performance in random generation and property optimization, implying its high capacity to model data distribution. Furthermore, MolHF is the first flow-based model that can be applied to model larger molecules (polymer) with more than 100 heavy atoms. The code and models are available at https://github.com/violet-sto/MolHF.

PAniC-3D: Stylized Single-view 3D Reconstruction from Portraits of Anime Characters

We propose PAniC-3D, a system to reconstruct stylized 3D character heads directly from illustrated (p)ortraits of (ani)me (c)haracters. Our anime-style domain poses unique challenges to single-view reconstruction; compared to natural images of human heads, character portrait illustrations have hair and accessories with more complex and diverse geometry, and are shaded with non-photorealistic contour lines. In addition, there is a lack of both 3D model and portrait illustration data suitable to train and evaluate this ambiguous stylized reconstruction task. Facing these challenges, our proposed PAniC-3D architecture crosses the illustration-to-3D domain gap with a line-filling model, and represents sophisticated geometries with a volumetric radiance field. We train our system with two large new datasets (11.2k Vroid 3D models, 1k Vtuber portrait illustrations), and evaluate on a novel AnimeRecon benchmark of illustration-to-3D pairs. PAniC-3D significantly outperforms baseline methods, and provides data to establish the task of stylized reconstruction from portrait illustrations.

Sample-efficient Multi-objective Molecular Optimization with GFlowNets

Many crucial scientific problems involve designing novel molecules with desired properties, which can be formulated as an expensive black-box optimization problem over the discrete chemical space. Computational methods have achieved initial success but still struggle with simultaneously optimizing multiple competing properties in a sample-efficient manner. In this work, we propose a multi-objective Bayesian optimization (MOBO) algorithm leveraging the hypernetwork-based GFlowNets (HN-GFN) as an acquisition function optimizer, with the purpose of sampling a diverse batch of candidate molecular graphs from an approximate Pareto front. Using a single preference-conditioned hypernetwork, HN-GFN learns to explore various trade-offs between objectives. Inspired by reinforcement learning, we further propose a hindsight-like off-policy strategy to share high-performing molecules among different preferences in order to speed up learning for HN-GFN. Through synthetic experiments, we illustrate that HN-GFN has adequate capacity to generalize over preferences. Extensive experiments show that our framework outperforms the best baselines by a large margin in terms of hypervolume in various real-world MOBO settings.