arXiv subjects

Zaixiang Zheng

Publications and source records attributed to Zaixiang Zheng.

At least 19 recordsLinked to original sources

arXiv2026

Towards A Generative Protein Evolution Machine with DPLM-Evo

Proteins are shaped by gradual evolution under biophysical and functional constraints. Protein language models learn rich evolutionary constraints from large-scale sequences, and discrete diffusion-based protein language models~(\eg, DPLMs) are promising for both understanding and generation. However, existing DPLMs typically rely on masked diffusion that contradicts a simple biological intuition: proteins evolve through accumulated edits, not by emerging from masks. Consequently, these frameworks lack explicit pretraining objectives for substitution and insertion/deletion (indel) operations, limiting both optimization-style post-editing and flexible guided generation. To address these limitations, we present DPLM-Evo, an evolutionary discrete diffusion framework that explicitly predicts substitution, insertion, and deletion operations during denoising. DPLM-Evo decouples an upsampled-length latent alignment space from the variable-length observed sequence space, which makes indel-aware generation tractable. To better align substitutions with real evolution, we further introduce a contextualized evolutionary noising kernel that produces biologically informed, context-dependent mutation patterns. Across tasks, DPLM-Evo improves sequence understanding and achieves state-of-the-art mutation effect prediction performance on ProteinGym in the single-sequence setting. It also enables variable-length simulated evolution, and post-editing/optimization of existing proteins via explicit edit trajectories.

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arXiv2026

Protein Autoregressive Modeling via Multiscale Structure Generation

We present protein autoregressive modeling (PAR), the first multi-scale autoregressive framework for protein backbone generation via coarse-to-fine next-scale prediction. Using the hierarchical nature of proteins, PAR generates structures that mimic sculpting a statue, forming a coarse topology and refining structural details over scales. To achieve this, PAR consists of three key components: (i) multi-scale downsampling operations that represent protein structures across multiple scales during training; (ii) an autoregressive transformer that encodes multi-scale information and produces conditional embeddings to guide structure generation; (iii) a flow-based backbone decoder that generates backbone atoms conditioned on these embeddings. Moreover, autoregressive models suffer from exposure bias, caused by the training and the generation procedure mismatch, and substantially degrades structure generation quality. We effectively alleviate this issue by adopting noisy context learning and scheduled sampling, enabling robust backbone generation. Notably, PAR exhibits strong zero-shot generalization, supporting flexible human-prompted conditional generation and motif scaffolding without requiring fine-tuning. On the unconditional generation benchmark, PAR effectively learns protein distributions and produces backbones of high design quality, and exhibits favorable scaling behavior. Together, these properties establish PAR as a promising framework for protein structure generation.

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arXiv2025

An All-Atom Generative Model for Designing Protein Complexes

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.

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arXiv2025

Elucidating the Design Space of Multimodal Protein Language Models

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/.

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arXiv2025

Designing Cyclic Peptides via Harmonic SDE with Atom-Bond Modeling

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.

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arXiv2025

Diffusion Language Models Can Perform Many Tasks with Scaling and Instruction-Finetuning

The recent surge of generative AI has been fueled by the generative power of diffusion probabilistic models and the scalable capabilities of large language models. Despite their potential, it remains elusive whether diffusion language models can solve general language tasks comparable to their autoregressive counterparts. This paper demonstrates that scaling diffusion models w.r.t. data, sizes, and tasks can effectively make them strong language learners. We build competent diffusion language models at scale by first acquiring knowledge from massive data via masked language modeling pretraining thanks to their intrinsic connections. We then reprogram pretrained masked language models into diffusion language models via diffusive adaptation, wherein task-specific finetuning and instruction finetuning are explored to unlock their versatility in solving general language tasks. Experiments show that scaling diffusion language models consistently improves performance across downstream language tasks. We further discover that instruction finetuning can elicit zero-shot and few-shot in-context learning abilities that help tackle many unseen tasks by following natural language instructions, and show promise in advanced and challenging abilities such as reasoning.

cs.CL↗

arXiv2025

Multilingual Non-Autoregressive Machine Translation without Knowledge Distillation

Multilingual neural machine translation (MNMT) aims at using one single model for multiple translation directions. Recent work applies non-autoregressive Transformers to improve the efficiency of MNMT, but requires expensive knowledge distillation (KD) processes. To this end, we propose an M-DAT approach to non-autoregressive multilingual machine translation. Our system leverages the recent advance of the directed acyclic Transformer (DAT), which does not require KD. We further propose a pivot back-translation (PivotBT) approach to improve the generalization to unseen translation directions. Experiments show that our M-DAT achieves state-of-the-art performance in non-autoregressive MNMT.

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arXiv2024

ProteinWeaver: A Divide-and-Assembly Approach for Protein Backbone Design

Nature creates diverse proteins through a 'divide and assembly' strategy. Inspired by this idea, we introduce ProteinWeaver, a two-stage framework for protein backbone design. Our method first generates individual protein domains and then employs an SE(3) diffusion model to flexibly assemble these domains. A key challenge lies in the assembling step, given the complex and rugged nature of the inter-domain interaction landscape. To address this challenge, we employ preference alignment to discern complex relationships between structure and interaction landscapes through comparative analysis of generated samples. Comprehensive experiments demonstrate that ProteinWeaver: (1) generates high-quality, novel protein backbones through versatile domain assembly; (2) outperforms RFdiffusion, the current state-of-the-art in backbone design, by 13\% and 39\% for long-chain proteins; (3) shows the potential for cooperative function design through illustrative case studies. To sum up, by introducing a `divide-and-assembly' paradigm, ProteinWeaver advances protein engineering and opens new avenues for functional protein design.

q-bio.BM↗

arXiv2024

Antigen-Specific Antibody Design via Direct Energy-based Preference Optimization

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.

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arXiv2024

DPLM-2: A Multimodal Diffusion Protein Language Model

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, as well as providing structure-aware representations for predictive tasks.

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arXiv2024

Diffusion Language Models Are Versatile Protein Learners

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 makes 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 (Lin et al., 2022). 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 conditioner, 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. Code is released at \url{https://github.com/bytedance/dplm}.

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arXiv2024

ProteinBench: A Holistic Evaluation of Protein Foundation Models

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.

q-bio.QM↗

arXiv2024

DINOISER: Diffused Conditional Sequence Learning by Manipulating Noises

While diffusion models have achieved great success in generating continuous signals such as images and audio, it remains elusive for diffusion models in learning discrete sequence data like natural languages. Although recent advances circumvent this challenge of discreteness by embedding discrete tokens as continuous surrogates, they still fall short of satisfactory generation quality. To understand this, we first dive deep into the denoised training protocol of diffusion-based sequence generative models and determine their three severe problems, i.e., 1) failing to learn, 2) lack of scalability, and 3) neglecting source conditions. We argue that these problems can be boiled down to the pitfall of the not completely eliminated discreteness in the embedding space, and the scale of noises is decisive herein. In this paper, we introduce DINOISER to facilitate diffusion models for sequence generation by manipulating noises. We propose to adaptively determine the range of sampled noise scales for counter-discreteness training; and encourage the proposed diffused sequence learner to leverage source conditions with amplified noise scales during inference. Experiments show that DINOISER enables consistent improvement over the baselines of previous diffusion-based sequence generative models on several conditional sequence modeling benchmarks thanks to both effective training and inference strategies. Analyses further verify that DINOISER can make better use of source conditions to govern its generative process.

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arXiv2023

Structure-informed Language Models Are Protein Designers

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 up 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)

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arXiv2022

Helping the Weak Makes You Strong: Simple Multi-Task Learning Improves Non-Autoregressive Translators

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 multi-task 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.

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arXiv2022

Duplex Sequence-to-Sequence Learning for Reversible Machine Translation

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 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.

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arXiv2021

Vocabulary Learning via Optimal Transport for Neural Machine Translation

The choice of token vocabulary affects the performance of machine translation. This paper aims to figure out what is a good vocabulary and whether one can find the optimal vocabulary without trial training. To answer these questions, we first provide an alternative understanding of the role of vocabulary from the perspective of information theory. Motivated by this, we formulate the quest of vocabularization -- finding the best token dictionary with a proper size -- as an optimal transport (OT) problem. We propose VOLT, a simple and efficient solution without trial training. Empirical results show that VOLT outperforms widely-used vocabularies in diverse scenarios, including WMT-14 English-German and TED's 52 translation directions. For example, VOLT achieves almost 70% vocabulary size reduction and 0.5 BLEU gain on English-German translation. Also, compared to BPE-search, VOLT reduces the search time from 384 GPU hours to 30 GPU hours on English-German translation. Codes are available at https://github.com/Jingjing-NLP/VOLT .

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arXiv2021

The Volctrans GLAT System: Non-autoregressive Translation Meets WMT21

This paper describes the Volctrans' submission to the WMT21 news translation shared task for German->English translation. We build a parallel (i.e., non-autoregressive) translation system using the Glancing Transformer, which enables fast and accurate parallel decoding in contrast to the currently prevailing autoregressive models. To the best of our knowledge, this is the first parallel translation system that can be scaled to such a practical scenario like WMT competition. More importantly, our parallel translation system achieves the best BLEU score (35.0) on German->English translation task, outperforming all strong autoregressive counterparts.

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