Proteins are essential macromolecules defined by their amino acid sequences, which determine their three-dimensional structures and, consequently, their functions in all living organisms. Therefore, generative protein modeling necessitates a multimodal approach to simultaneously model, understand, and generate both sequences and structures. However, existing methods typically use separate models for each modality, limiting their ability to capture the intricate relationships between sequence and structure. This results in suboptimal performance in tasks that requires joint understanding and generation of both modalities. In this paper, we introduce DPLM-2, a multimodal protein foundation model that extends discrete diffusion protein language model (DPLM) to accommodate both sequences and structures. To enable structural learning with the language model, 3D coordinates are converted to discrete tokens using a lookup-free quantization-based tokenizer. By training on both experimental and high-quality synthetic structures, DPLM-2 learns the joint distribution of sequence and structure, as well as their marginals and conditionals. We also implement an efficient warm-up strategy to exploit the connection between large-scale evolutionary data and structural inductive biases from pre-trained sequence-based protein language models. Empirical evaluation shows that DPLM-2 can simultaneously generate highly compatible amino acid sequences and their corresponding 3D structures eliminating the need for a two-stage generation approach. Moreover, DPLM-2 demonstrates competitive performance in various conditional generation tasks, including folding, inverse folding, and scaffolding with multimodal motif inputs.

Recent years have witnessed a surge in the development of protein foundation models, significantly improving performance in protein prediction and generative tasks ranging from 3D structure prediction and protein design to conformational dynamics. However, the capabilities and limitations associated with these models remain poorly understood due to the absence of a unified evaluation framework. To fill this gap, we introduce ProteinBench, a holistic evaluation framework designed to enhance the transparency of protein foundation models. Our approach consists of three key components: (i) A taxonomic classification of tasks that broadly encompass the main challenges in the protein domain, based on the relationships between different protein modalities; (ii) A multi-metric evaluation approach that assesses performance across four key dimensions: quality, novelty, diversity, and robustness; and (iii) In-depth analyses from various user objectives, providing a holistic view of model performance. Our comprehensive evaluation of protein foundation models reveals several key findings that shed light on their current capabilities and limitations. To promote transparency and facilitate further research, we release the evaluation dataset, code, and a public leaderboard publicly for further analysis and a general modular toolkit. We intend for ProteinBench to be a living benchmark for establishing a standardized, in-depth evaluation framework for protein foundation models, driving their development and application while fostering collaboration within the field.

Proteins typically exist in complexes, interacting with other proteins or biomolecules to perform their specific biological roles. Research on single-chain protein modeling has been extensively and deeply explored, with advancements seen in models like the series of ESM and AlphaFold2. Despite these developments, the study and modeling of multi-chain proteins remain largely uncharted, though they are vital for understanding biological functions. Recognizing the importance of these interactions, we introduce APM (all-Atom Protein generative Model), a model specifically designed for modeling multi-chain proteins. By integrating atom-level information and leveraging data on multi-chain proteins, APM is capable of precisely modeling inter-chain interactions and designing protein complexes with binding capabilities from scratch. It also performs folding and inverse-folding tasks for multi-chain proteins. Moreover, APM demonstrates versatility in downstream applications: it achieves enhanced performance through supervised fine-tuning (SFT) while also supporting zero-shot sampling in certain tasks, achieving state-of-the-art results. We released our code at https://github.com/bytedance/apm.

Multimodal protein language models (PLMs) integrate sequence and token-based structural information, serving as a powerful foundation for protein modeling, generation, and design. However, the reliance on tokenizing 3D structures into discrete tokens causes substantial loss of fidelity about fine-grained structural details and correlations. In this paper, we systematically elucidate the design space of multimodal PLMs to overcome their limitations. We identify tokenization loss and inaccurate structure token predictions by the PLMs as major bottlenecks. To address these, our proposed design space covers improved generative modeling, structure-aware architectures and representation learning, and data exploration. Our advancements approach finer-grained supervision, demonstrating that token-based multimodal PLMs can achieve robust structural modeling. The effective design methods dramatically improve the structure generation diversity, and notably, folding abilities of our 650M model by reducing the RMSD from 5.52 to 2.36 on PDB testset, even outperforming 3B baselines and on par with the specialized folding models. Project page and code: https://bytedance.github.io/dplm/dplm-2.1.

Cyclic peptides offer inherent advantages in pharmaceuticals. For example, cyclic peptides are more resistant to enzymatic hydrolysis compared to linear peptides and usually exhibit excellent stability and affinity. Although deep generative models have achieved great success in linear peptide design, several challenges prevent the development of computational methods for designing diverse types of cyclic peptides. These challenges include the scarcity of 3D structural data on target proteins and associated cyclic peptide ligands, the geometric constraints that cyclization imposes, and the involvement of non-canonical amino acids in cyclization. To address the above challenges, we introduce CpSDE, which consists of two key components: AtomSDE, a generative structure prediction model based on harmonic SDE, and ResRouter, a residue type predictor. Utilizing a routed sampling algorithm that alternates between these two models to iteratively update sequences and structures, CpSDE facilitates the generation of cyclic peptides. By employing explicit all-atom and bond modeling, CpSDE overcomes existing data limitations and is proficient in designing a wide variety of cyclic peptides. Our experimental results demonstrate that the cyclic peptides designed by our method exhibit reliable stability and affinity.

This paper introduces diffusion protein language model (DPLM), a versatile protein language model that demonstrates strong generative and predictive capabilities for protein sequences. We first pre-train scalable DPLMs from evolutionary-scale protein sequences within a generative self-supervised discrete diffusion probabilistic framework, which generalizes language modeling for proteins in a principled way. After pre-training, DPLM exhibits the ability to generate structurally plausible, novel and diverse protein sequences for unconditional generation. We further demonstrate the proposed diffusion generative pre-training make DPLM possess a better understanding of proteins, making it a superior representation learner, which can be fine-tuned for various predictive tasks, comparing favorably to ESM2. Moreover, DPLM can be tailored for various needs, which showcases its prowess of conditional generation in several ways: (1) conditioning on partial peptide sequences, e.g., generating scaffolds for functional motifs with high success rate; (2) incorporating other modalities as conditioners, e.g., structure-conditioned generation for inverse folding; and (3) steering sequence generation towards desired properties, e.g., satisfying specified secondary structures, through a plug-and-play classifier guidance.

Antibody design, a crucial task with significant implications across various disciplines such as therapeutics and biology, presents considerable challenges due to its intricate nature. In this paper, we tackle antigen-specific antibody sequence-structure co-design as an optimization problem towards specific preferences, considering both rationality and functionality. Leveraging a pre-trained conditional diffusion model that jointly models sequences and structures of antibodies with equivariant neural networks, we propose direct energy-based preference optimization to guide the generation of antibodies with both rational structures and considerable binding affinities to given antigens. Our method involves fine-tuning the pre-trained diffusion model using a residue-level decomposed energy preference. Additionally, we employ gradient surgery to address conflicts between various types of energy, such as attraction and repulsion. Experiments on RAbD benchmark show that our approach effectively optimizes the energy of generated antibodies and achieves state-of-the-art performance in designing high-quality antibodies with low total energy and high binding affinity simultaneously, demonstrating the superiority of our approach.

This paper demonstrates that language models are strong structure-based protein designers. We present LM-Design, a generic approach to reprogramming sequence-based protein language models (pLMs), that have learned massive sequential evolutionary knowledge from the universe of natural protein sequences, to acquire an immediate capability to design preferable protein sequences for given folds. We conduct a structural surgery on pLMs, where a lightweight structural adapter is implanted into pLMs and endows it with structural awareness. During inference, iterative refinement is performed to effectively optimize the generated protein sequences. Experiments show that LM-Design improves the state-of-the-art results by a large margin, leading to 4% to 12% accuracy gains in sequence recovery (e.g., 55.65%/56.63% on CATH 4.2/4.3 single-chain benchmarks, and $>$60% when designing protein complexes). We provide extensive and in-depth analyses, which verify that LM-Design can (1) indeed leverage both structural and sequential knowledge to accurately handle structurally non-deterministic regions, (2) benefit from scaling data and model size, and (3) generalize to other proteins (e.g., antibodies and de novo proteins).

Recently, non-autoregressive (NAR) neural machine translation models have received increasing attention due to their efficient parallel decoding.However, the probabilistic framework of NAR models necessitates conditional independence assumption on target sequences, falling short of characterizing human language data.This drawback results in less informative learning signals for NAR models under conventional MLE training, thereby yielding unsatisfactory accuracy compared to their autoregressive (AR) counterparts.In this paper, we propose a simple and model-agnostic multitask learning framework to provide more informative learning signals.During training stage, we introduce a set of sufficiently weak AR decoders that solely rely on the information provided by NAR decoder to make prediction, forcing the NAR decoder to become stronger or else it will be unable to support its weak AR partners.Experiments on WMT and IWSLT datasets show that our approach can consistently improve accuracy of multiple NAR baselines without adding any additional decoding overhead.

Machine Translation Quality Estimation (QE) is a task of predicting the quality of machine translations without relying on any reference. Recently, the predictor-estimator framework trains the predictor as a feature extractor, which leverages the extra parallel corpora without QE labels, achieving promising QE performance. However, we argue that there are gaps between the predictor and the estimator in both data quality and training objectives, which preclude QE models from benefiting from a large number of parallel corpora more directly. We propose a novel framework called DirectQE that provides a direct pretraining for QE tasks. In DirectQE, a generator is trained to produce pseudo data that is closer to the real QE data, and a detector is pretrained on these data with novel objectives that are akin to the QE task. Experiments on widely used benchmarks show that DirectQE outperforms existing methods, without using any pretraining models such as BERT. We also give extensive analyses showing how fixing the two gaps contributes to our improvements.

Jingjing Xu, Hao Zhou, Chun Gan, Zaixiang Zheng, Lei Li. Proceedings of the 59th Annual Meeting of the Association for Computational Linguistics and the 11th International Joint Conference on Natural Language Processing (Volume 1: Long Papers). 2021.

Sequence-to-sequence learning naturally has two directions. How to effectively utilize supervision signals from both directions? Existing approaches either require two separate models, or a multitask-learned model but with inferior performance. In this paper, we propose REDER (Reversible Duplex Transformer), a parameter-efficient model and apply it to machine translation. Either end of REDER can simultaneously input and output a distinct language. Thus REDER enables {\em reversible machine translation} by simply flipping the input and output ends. Experiments verify that REDER achieves the first success of reversible machine translation, which helps outperform its multitask-trained baselines by up to 1.3 BLEU.

Document-level machine translation manages to outperform sentence level models by a small margin, but have failed to be widely adopted. We argue that previous research did not make a clear use of the global context, and propose a new document-level NMT framework that deliberately models the local context of each sentence with the awareness of the global context of the document in both source and target languages. We specifically design the model to be able to deal with documents containing any number of sentences, including single sentences. This unified approach allows our model to be trained elegantly on standard datasets without needing to train on sentence and document level data separately. Experimental results demonstrate that our model outperforms Transformer baselines and previous document-level NMT models with substantial margins of up to 2.1 BLEU on state-of-the-art baselines. We also provide analyses which show the benefit of context far beyond the neighboring two or three sentences, which previous studies have typically incorporated.

Recently, self-attention networks show strong advantages of sentence modeling in many NLP tasks. However, self-attention mechanism computes the interactions of every pair of words independently regardless of their positions, which makes it not able to capture the sequential relations between words in different positions in a sentence. In this paper, we improve the self-attention networks by better integrating sequential relations, which is essential for modeling natural languages. Specifically, we 1) propose a position-based attention to model the interaction between two words regarding positions; 2) perform separated attention for the context before and after the current position, respectively; and 3) merge the above two parts with a position-aware gated fusion mechanism. Experiments in natural language inference, machine translation and sentiment analysis tasks show that our sequential relation modeling helps self-attention networks outperform existing approaches. We also provide extensive analyses to shed light on what the models have learned about the sequential relations.

Relation detection is a core step in many natural language process applications including knowledge base question answering.Previous efforts show that single-fact questions could be answered with high accuracy.However, one critical problem is that current approaches only get high accuracy for questions whose relations have been seen in the training data.But for unseen relations, the performance will drop rapidly.The main reason for this problem is that the representations for unseen relations are missing.In this paper, we propose a simple mapping method, named representation adapter, to learn the representation mapping for both seen and unseen relations based on previously learned relation embedding.We employ the adversarial objective and the reconstruction objective to improve the mapping performance.We re-organize the popular Sim-pleQuestion dataset to reveal and evaluate the problem of detecting unseen relations.Experiments show that our method can greatly improve the performance of unseen relations while the performance for those seen part is kept comparable to the state-of-the-art. 1

Zaixiang Zheng, Shujian Huang, Zhaopeng Tu, Xin-Yu Dai, Jiajun Chen. Proceedings of the 2019 Conference on Empirical Methods in Natural Language Processing and the 9th International Joint Conference on Natural Language Processing (EMNLP-IJCNLP). 2019.

Existing neural machine translation systems do not explicitly model what has been translated and what has not during the decoding phase. To address this problem, we propose a novel mechanism that separates the source information into two parts: translated Past contents and untranslated Future contents, which are modeled by two additional recurrent layers. The Past and Future contents are fed to both the attention model and the decoder states, which provides Neural Machine Translation (NMT) systems with the knowledge of translated and untranslated contents. Experimental results show that the proposed approach significantly improves the performance in Chinese-English, German-English, and English-German translation tasks. Specifically, the proposed model outperforms the conventional coverage model in terms of both the translation quality and the alignment error rate.

In the encoder-decoder architecture for neural machine translation (NMT), the hidden states of the recurrent structures in the encoder and decoder carry the crucial information about the sentence.These vectors are generated by parameters which are updated by back-propagation of translation errors through time.We argue that propagating errors through the end-to-end recurrent structures are not a direct way of control the hidden vectors.In this paper, we propose to use word predictions as a mechanism for direct supervision.More specifically, we require these vectors to be able to predict the vocabulary in target sentence.Our simple mechanism ensures better representations in the encoder and decoder without using any extra data or annotation.It is also helpful in reducing the target side vocabulary and improving the decoding efficiency.Experiments on Chinese-English and German-English machine translation tasks show BLEU improvements by 4.53 and 1.3, respectively.