Protein Structure Generation

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20 papers5 papers in the last four weeks, against 1 the four weeks before. 0.0% of all new papers.

Oct 22, 2026

Trion-1: Unifying Language, Protein Sequence, and Structure with Diffusion Language Models

We envision a general-purpose protein foundation model as a unified, interactive model of sequence, structure, and function, capable of understanding, generation, and cross-modal translation while retaining the instruction-following and reasoning capabilities of modern LLMs. Toward this vision, we introduce Trion-1, the first native, unified, multimodal diffusion language model (dLLM) for proteins. Trion-1 is built on two key design choices: (1) a unified discrete token space that jointly represents sequence, structure, and natural language; (2) a dLLM backbone that replaces strict left-to-right factorization with bidirectional or semi-bidirectional token interactions, enabling global residue communication and long-range contact modeling that are naturally suited to structure modeling. This formulation unifies six core capabilities: folding, inverse folding, sequence understanding, structure understanding, sequence design, and structure design, while retaining the native language capabilities of general-purpose LLMs. On established benchmarks, Trion-1 achieves broadly competitive performance. In folding, Trion-1 achieves a TM-score above 0.8 with a single sample under strict homology control, matching or exceeding the existing tri-modal model using 200 samples. For sequence understanding, Trion-1 performs on par with top-tier LLMs such as Claude Opus 4.7 (62.37%). These results support well-aligned sequence-structure-language representations and strong cross-modal generative capabilities.

Tianyu Lu, Kaicheng Yang, Jiangtao Feng +7

Protein Language Models Protein Structure Generation Diffusion Language Models Protein Representation Learning Multimodal Diffusion Models Protein Structure Prediction+1

Oct 16, 2026

ADT: All-Atom Diffusion Tokenizer for 3D Molecular Structures

Discrete structural tokenization provides a promising route to autoregressive 3D molecular generation. Yet, existing tokenizers face a trade-off between compact representation and all-atom reconstruction: atom-level tokens preserve atomic details but produce long sequences, while compact residue-level protein tokens typically omit side-chain geometry. To overcome this limitation, we propose All-atom Diffusion Tokenizer (ADT), which decouples token granularity from reconstruction resolution. ADT uses one structural token per atom for small molecules and one token per protein residue that jointly represents backbone and side-chain geometry. To mitigate geometric distortion introduced by quantization, we leverage the generative capacity of diffusion models to recover fine-grained atomic geometry beyond deterministic decoding from discrete tokens. Extensive experiments across small molecules and proteins demonstrate that ADT achieves strong reconstruction from compact discrete representations while enabling high-quality autoregressive generation of both small molecules and all-atom protein structures. These results establish compact structural tokens as an effective discrete interface for all-atom molecular reconstruction and generation.

Xuantuo Huang, Encheng Su, Aoran Wang +6

Peking University · University of Science and Technology of China · Shanghai AI Laboratory +1

Protein Structure Generation 3D Molecular Generation Generative Modeling Molecular Representation Learning 3D Diffusion Models

Oct 11, 2026

DC-Flow: Target-Conditioned Cyclic Peptide Design via Delayed-Coupling Flow Matching

Target-conditioned cyclic peptide design requires coordinating interfacial side chains with macrocyclic closure. Existing end-to-end generators concurrently update geometric and chemical variables from noise, assigning residues to disordered coordinates. Meanwhile, predictor-assisted workflows often get stuck in local traps because they lack feedback in the propose-and-filter stage and ignore 3D structural proposals during sequence search. To overcome the drawbacks of these two paradigms, we propose DC-FLOW, a staged generative framework built around Delayed-Coupling Flow Matching. In principle, DC-FLOW postpones sequence and side-chain activation until a target-conditioned backbone takes shape, resolving structural ambiguity before chemical assignment. Then, it feeds delayed activations back into the backbone, achieving co-evolution of backbone geometry and emerging residue identities by coupling their flows. This mechanism enables more reliable macrocyclic closure and favorable interface packing. For predictor-assisted workflows, DC-FLOW supplies 3D proposals with in-trajectory guidance, enabling cascaded test-time scaling to prune redundant backbones and terminate unpromising refinement early. Extensive experiments show that DC-FLOW improves cyclization fidelity, diversity, and interface energetics, substantially increasing the yield of confident cyclic peptide binders under a fixed final-candidate budget. Our code is available at https://github.com/mianqiu00/DCFlow.

Yitian Wang, Minjie Cheng, Yaning Cui +3

Gaoling School of Artificial Intelligence, Renmin University of China · DP Technology · Cyclon Therapeutics +2

Protein Structure Generation Molecular Generation Generative Modeling Protein Design Protein Binder Design Conditional Flow Matching

Oct 9, 2026

Designing Protein Structures from Natural Language

A central challenge in de novo protein design is generating proteins with desired structural and functional properties. Existing design models typically require a dedicated input representation for each property, limiting the design objectives they support. We develop Prompteina, the first all-atom structure generation model that supports new and broader design objectives specified in natural language, analogous to text-to-image generation. To train Prompteina, we construct Prompteina-Data, a paired text--protein structure dataset of 1.8M structures and 50M+ captions describing global and residue-specific structural and functional properties. We adapt Proteina-Complexa, a pretrained structure generation model, through text-conditioned pretraining and finetuning that aligns residues with their corresponding text. Prompteina outperforms baselines on 15 of 18 structural properties and generates proteins that more closely match descriptions of their intended functions. In binder design, it leads baselines on at least 13 of 20 targets and improves interface confidence by 14% over the strongest baseline. With iterative in silico feedback, Prompteina's gain over non-iterative generation is 57% larger than the next-best baseline on the hardest targets. Finally, we experimentally validate Prompteina designs against GM2A, a target with no reported de novo binders. We identify nine binders, with the strongest at an apparent

K_{\mathrm{D}}

of 107 nM. These results establish natural language as an effective and powerful conditioning interface for protein structure generation.

Joseph Lee, Yanjing Li, Bo Qiang +7

University of Washington · National University of Singapore · Allen Institute for AI (Ai2) +1

Protein Structure Generation Protein Design Generative Modeling Protein Binder Design

Oct 2, 2026

Learning Latent Protein Languages for Autoregressive Generation

Autoregressive transformers remain comparatively weak for protein sequence and structure generation. We study the role of target representation: amino acid tokens encode residue identities without explicit contextual semantics, while backbone coordinates require a discrete representation in our framework. We introduce two learned latent protein languages. Protein Latent Language (PLL) maps sequences to a 4,096-state contextual alphabet built on a frozen ESM-2 encoder, with one token per residue. Structure Latent Language (SLL) adapts GCP-VQVAE Lite with auxiliary sequence and confidence supervision while retaining decoding to backbone coordinates. We separately pretrain autoregressive transformer models on PLL and SLL tokens using next-token prediction, yielding PLLM and SLLM. Under matched downstream sequence training, PLLM has a fitted compute-scaling exponent of 0.038 versus 0.020 for the amino acid autoregressive model. In unconditional sequence generation, PLLM reduces the fraction of samples below a heuristic 1.5-bit residue-composition entropy threshold by 54% relative to the amino acid model across sampling temperatures. For sequence-to-structure prediction, replacing the original GCP-VQVAE Lite tokenizer with SLL reduces best validation perplexity by 34% under matched training. For long proteins, latent-token sampling is approximately 1,000 times faster than MSA-based AlphaFold2 in our measurements. In backbone generation, SLLM compares favorably with other generative models on diversity and novelty. We also observe early signs that using SLLM's internal token confidence for inference-time sampling can improve sequence-to-structure prediction quality beyond a single decoded sample. These results position learned latent protein languages as a promising substrate for autoregressive transformer scaling and inference-time sampling in protein generation.

Mahdi Pourmirzaei, Farzaneh Esmaili, Amir Ziashahabi +2

University of Missouri · University of Southern California · Independent Researcher

Protein Structure Generation Protein Language Models Molecular Generation Generative Modeling Protein Representation Learning Autoregressive Language Modeling+1

Sep 26, 2026

PhiFold: Towards Dynamic Protein Design with Physics-Structured Covariance Modeling

Protein design is moving beyond structural correctness toward function-aware design, yet existing generative models typically treat dynamics as a downstream property estimated through simulation or prediction after structure generation. Using MD trajectories as a generative target is also undesirable because stochastic, path-dependent trajectories over-specify the underlying equilibrium ensemble. We introduce PhiFold, a framework for jointly generating protein backbones and their second-order dynamics, represented by residue-displacement covariance. Rather than predicting the quadratically sized full covariance, PhiFold decomposes dynamics into three interpretable components: local flexibility, a low-rank collective-motion representation, and residue-wise collective participation. These components are assembled into a positive-definite covariance matrix with exact marginal consistency, yielding a compact and physically constrained representation of equilibrium dynamics. Across generated proteins, PhiFold improves recovery of local fluctuations and long-range residue coupling while remaining competitive on dominant collective-motion subspaces. It further enables bidirectional control of residue flexibility while preserving backbone designability. By unifying structure generation with an explicit representation of equilibrium dynamics, PhiFold lays a foundation for designing proteins not only by how they look, but also by how they move.

Yutian Liu, Mujie Lin, LanqianZhang +4

School of Computer Science, Peking University, Beijing, China · School of Electronic and Computer Engineering, Peking University, Shenzhen, China · School of Life Sciences, Tsinghua University, Beijing 100084, China +2

Protein Design Protein Structure Generation Physics-Informed Generative Modeling Covariance Estimation

Jun 12, 2026

Emyx: Fast and efficient all-atom protein generation

Computational enzyme design requires generating proteins that scaffold catalytic residues and ligands, a task that demands both geometric accuracy and structural diversity from the underlying generative model. Current all-atom generators inherit expensive architectures from structure prediction, leading to high training costs and limited sample diversity. We argue that much of this complexity is unnecessary for generators, which condition on sparse geometric constraints rather than rich co-evolutionary signals. Emyx is a 140M-parameter conditional flow matching model that concentrates capacity within standard transformer blocks, replacing heavy embedding stacks with lightweight conditional representations and sparse connectivity. We additionally derive an exact reparametrisation of the flow matching interpolant into the EDM noise-level framework, bridging flow matching training efficiency with state-of-the-art sampling methods designed for diffusion models without retraining. Despite being the smallest model, Emyx outperforms both Proteína-Complexa and RFdiffusion3 against the AME enzyme design benchmark across success rate under strict evaluation requiring both global fold recovery and catalytic geometry accuracy, structural novelty, scaffold diversity, and geometric validity, while training in just

682

GPU-hours, roughly

4\times

less than RFdiffusion3.

Nicholas J. Williams, Ward Haddadin, Matteo P. Ferla +6

Xyme, Oxford, UK

Conditional Flow Matching 3D Molecular Generation Flow-Based Generative Modeling Protein Design Protein Structure Generation

Jun 3, 2026

ProHiFlo: Hierarchical Flow Matching with Functional Guidance for De Novo Protein Generation

De novo protein generation has transformative potential in therapeutic design, enzyme engineering, and synthetic biology. While diffusion-based and flow matching approaches have achieved progress, they typically operate at single resolution and lack mechanisms for incorporating functional constraints. We introduce ProHiFlo, a hierarchical flow matching framework with three innovations: (1) coarse-to-fine generation that models backbone geometry before refining to all-atom coordinates, reducing computational cost while maintaining accuracy; (2) functional guidance leveraging pretrained predictors to steer generation toward desired properties without retraining; (3) adaptive SE(3)-equivariant architecture for efficient multi-scale processing. Experiments on unconditional generation, motif scaffolding, and functional design demonstrate state-ofthe-art performance while requiring 4 fewer sampling steps. On enzyme active site scaffolding, ProHiFlo achieves 58.9% success rate compared to 41.2% for RFDiffusion.

Chuanzhen Wang, Meade Cleti, Pete Jano

3Tongji University · 1Arizona State University · University of Wisconsin-Madison

Flow Matching 3D Molecular Generation Protein Design Conditional Generative Modeling Protein Structure Generation

May 18, 2026

DCFold: Efficient Protein Structure Generation with Single Forward Pass

AlphaFold3 introduces a diffusion-based architecture that elevates protein structure prediction to all-atom resolution with improved accuracy. This state-of-the-art performance has established AlphaFold3 as a foundation model for diverse generation and design tasks. However, its iterative design substantially increases inference time, limiting practical deployment in downstream settings such as virtual screening and protein design. We propose DCFold, a single-step generative model that attains AlphaFold3-level accuracy. Our Dual Consistency training framework, which incorporates a novel Temporal Geodesic Matching (TGM) scheduler, enables DCFold to achieve a 15x acceleration in inference while maintaining predictive fidelity. We validate its effectiveness across both structure prediction and binder design benchmarks.

Zhe Zhang, Yuanning Feng, Yuxuan Song +3

Institute for AI Industry Research (AIR), Tsinghua University · Department of Computer Science and Technology, Tsinghua University · School of Computer Science and Technology, Huazhong University of Science and Technology +1

Protein Structure Prediction Protein Structure Generation AI-Assisted Scientific Research One-Step Generative Modeling Generative Modeling Molecular Generation+3

May 15, 2026

Ligand-Conditioned Discrete Diffusion for Protein Sequence-Structure Co-Design

Proteins perform their biological functions through three-dimensional structures encoded by amino acid sequences, and ligand-binding protein co-design requires models that generate sequence-structure compatible proteins under explicit ligand constraints. Although continuous diffusion and flow-based models support ligand-aware design in coordinate or latent spaces, existing discrete diffusion protein language models mainly operate over sequence or structure tokens without direct small-molecule conditioning. We introduce \textbf{ProtLiD

^2

}, a Protein Ligand-conditioned Discrete Diffusion model for protein sequence-structure co-design. ProtLiD

^2

jointly generates amino-acid sequence and discrete structure tokens while incorporating ligand chemical and geometric information through geometry-aware cross-attention. Trained on over one million ligand-protein complexes, ProtLiD

^2

extends masked discrete diffusion to ligand-aware functional protein design. We further propose maximum confidence-margin guided ReMask decoding, an inference-time self-correction strategy that retains confident predictions and remasks uncertain tokens. ProtLiD

^2

improves global fold confidence over Complexa in whole-protein design, increasing TM-score from 0.672 to 0.802 and pLDDT from 64.55 to 73.00. In pocket co-design, ProtLiD

^2

reduces active-site BB-RMSD from 3.46/3.40Å for FAIR/PocketGen to 1.97Å, and improves ligand-aware pass rates over PocketGen from 14.86% to 59.73% and from 6.08% to 23.49% under stricter docking thresholds. These results support ligand-conditioned discrete diffusion as an effective token-space framework for functional protein co-design. Code will be available at https://github.com/auroua/ProtLiD.

Chen Wei, Fanding Xu, Minghao Sun +5

Xi’an University of Posts & Telecommunications · National University of Singapore · Xi’an Jiaotong University +1

Protein Language Models Diffusion Language Model Decoding Molecular Generation Diffusion Language Models Protein Design Protein Structure Generation

May 15, 2026

CrystalBoltz: End-to-End Protein Structure Determination via Experiment-Guided Diffusion for X-Ray Crystallography

Generative models trained on public databases of protein structures, most of which have been determined by X-ray crystallography, now provide powerful priors for structure prediction. However, they are not readily conditioned on the measurements from a new crystallographic experiment, limiting their use for X-ray structure determination. In crystallography, the measured structure-factor amplitudes do not by themselves determine an electron density map or atomic structure because the associated phases are unobserved and must be inferred. Structure determination therefore remains an inverse problem in which candidate models must be both structurally plausible and consistent with measured diffraction data, often requiring substantial manual refinement by human experts. Emerging methods aim to incorporate experimental information more directly into predictive and refinement workflows. We present CrystalBoltz, a generative framework that casts crystallographic refinement as Bayesian inference over atomic structures and operates directly on structure-factor amplitudes. CrystalBoltz moves from unguided generation with a pre-trained prior over protein structures to experiment-guided posterior sampling, followed by atomic coordinate and B-factor refinement. Across multiple protein crystallography datasets, CrystalBoltz attains lower coordinate RMSD and lower R-factors than the strongest baselines considered, while reducing runtime by a factor of 33 relative to existing experimentally guided refinement.

Minseo Kim, Huanghao Mai, Jay Shenoy +3

Stanford University · SLAC National Accelerator Laboratory · UC Davis

Bayesian Inverse Problems Diffusion Posterior Sampling Protein Structure Generation

May 11, 2026

Yeti: A compact protein structure tokenizer for reconstruction and multi-modal generation

Multimodal models that jointly reason over protein sequences, structures, and function annotations within a unified representation hold immense potential for integrating multimodal data and generating new proteins with designed functional properties. To utilize transformer architectures, such models require a tokenizer that converts protein structure from continuous atomic coordinates into discrete representations suitable for scalable multimodal training. The quality of such models are fundamentally upper bounded by the fidelity and expressiveness of the underlying tokenized structure. However, existing tokenizers prioritize reconstruction over generative abilities. To address these gaps, we introduce Yeti, a simple and compact protein structure tokenizer based on lookup free quantization and trained end to end with a flow matching objective for multimodal learning. Compared to existing models, Yeti generally achieves the best codebook utilization and token diversity, and second best reconstruction accuracy (with 10x fewer parameters than ESM3) on diverse datasets. To validate Yeti's generative capability, we trained a compact multimodal model jointly over its structure tokens and amino acid sequence entirely from scratch, with no pretrained initialization. The resulting multimodal model generates plausible structures under unconditional cogeneration of protein sequence and structures, achieving comparable results to 10x larger models. Together, these results demonstrate that Yeti is a compact and expressive protein structure tokenizer suitable for training multimodal models that cogenerates highly plausible sequences and structures.

Nabin Giri, Steven Farrell, Kristofer E. Bouchard

Lawrence Berkeley National Laboratory

Protein Structure Generation Generative Modeling Multimodal Generation

May 5, 2026

A-CODE: Fully Atomic Protein Co-Design with Unified Multimodal Diffusion

We present A-CODE, a fully atomic unified one-stage protein co-design model that simultaneously refines discrete atom types and continuous atom coordinates. Unlike predominant two-stage methods that cascade structure design with amino acid-level sequence design, our approach is fully atomic within a unified multimodal diffusion framework, in which residue identities are inferred solely from atom-level predictions. Built upon the powerful all-atom architecture, A-CODE achieves superior designability for unconditional protein generation, outperforming all existing one-stage and two-stage design models. For binder design, A-CODE rivals and even outperforms existing state-of-the-art two-stage design models and, compared with the existing one-stage co-design model, achieves a drastic tenfold improvement in success rate on hard tasks. The inherent flexibility of our atomic formulation enables, for the first time, seamless adaptation to non-canonical amino acid (ncAA) modeling. Our fully atomic framework establishes a new, versatile foundation for all-atom generative modeling that can be naturally extended to complex biomolecular systems.

Chaoran Cheng, Jiaqi Guan, Milong Ren +5

University of Illinois Urbana-Champaign · 2ByteDance Seed

Protein Structure Generation Generative Modeling Molecular Generation Protein Design Protein Binder Design Multimodal Diffusion Models

May 1, 2026

Co-Generative De Novo Functional Protein Design

De novo functional protein design aims to generate protein sequences that realize specified biochemical functions without relying on evolutionary templates, enabling broad applications in biotechnology and medicine. Existing approaches adopt either direct function-to-sequence mapping or decoupled structure-sequence generation strategies but often fail to achieve functionality and foldability simultaneously. To address this, we propose CodeFP, a Co-generative protein language model for de novo Functional Protein design that simultaneously decodes sequence and structure tokens, thereby enabling superior simultaneous realization of functionality and foldability. CodeFP utilizes functional local structures to enrich functional semantic encodings, overcoming the suboptimal translation of flat encodings into structure tokens, while introducing auxiliary functional supervision to alleviate training ambiguity stemming from the one-to-many structure-to-token mapping. Extensive experiments show that CodeFP consistently achieves average improvements of 6.1% in functional consistency and 3.2% in foldability over the strongest baseline.

Xinrui Chen, Yizhen Luo, Siqi Fan +1

Institute for AI Industry Research (AIR), Tsinghua University · Department of Computer Science and Technology, Tsinghua University · PharMolix Inc.

Protein Language Models Molecular Generation Protein Design Conditional Generative Modeling Protein Structure Generation

May 1, 2026

Proteo-R1: Reasoning Foundation Models for De Novo Protein Design

Deep learning in de novo protein design has achieved atomic-level fidelity. However, existing models remain largely non-deliberative: they directly synthesize molecular geometries without explicitly reasoning about which residues or interactions are functionally essential. As a result, design decisions are entangled with continuous sampling dynamics, limiting interpretability, controllability, and systematic reuse of biochemical knowledge. We introduce Proteo-R1, a reasoning-guided protein design framework that explicitly decouples molecular understanding from geometric generation. Proteo-R1 adopts a dual-expert architecture in which a multimodal large language model (MLLM) serves as an understanding expert, analyzing protein sequences, structures, and textual context to identify key functional residues that govern binding and specificity. These residue-level decisions are then passed as hard constraints to a separate diffusion-based generation expert, which performs conditional co-design while respecting the fixed interaction anchors. This factorization mirrors how human experts approach molecular engineering: first, reasoning about critical interactions, then optimizing geometry subject to those constraints. By operationalizing reasoning as explicit residue-level commitments rather than latent textual guidance, Proteo-R1 achieves stable, interpretable, and modular integration of LLM reasoning with state-of-the-art geometric generative models. Code, data, and demos are available at https://smiles724.github.io/r1/.

Fang Wu, Weihao Xuan, Heli Qi +26

Stanford University

Molecular Generation Generative Modeling 3D Molecular Generation Conditional Generative Modeling Protein Design Large Language Model-Guided Scientific Discovery+1

Apr 23, 2026

Quotient-Space Diffusion Models

Diffusion-based generative models have reformed generative AI, and also enabled new capabilities in the science domain, e.g., fast generation of 3D structures of molecules. In such tasks, there is often a symmetry in the system, identifying elements that can be converted by certain transformations as equivalent. Equivariant diffusion models guarantee a symmetric distribution, but miss the opportunity to make learning easier, while alignment-based simplification attempts fail to preserve the target distribution. In this work, we develop quotient-space diffusion models, a principled generative framework to fully handle and leverage symmetry. By viewing the intrinsic generation process on the quotient space, the exact construction that removes symmetry redundancy, the framework simplifies learning by allowing model output to have an arbitrary intra-equivalence-class movement, while generating the correct symmetric target distribution with guarantee. We instantiate the framework for molecular structure generation which follows

\mathrm{SE}(3)

(rigid-body movement) symmetry. It improves the performance over equivariant diffusion models and outperforms alignment-based methods universally for small molecules and proteins, representing a new framework that surpasses previous symmetry treatments in generative models.

Yixian Xu, Yusong Wang, Shengjie Luo +4

State Key Laboratory of General Artificial Intelligence, Peking University, Beijing, China · State Key Laboratory of Human-Machine Hybrid Augmented Intelligence, Institute of Artificial Intelligence and Robotics, Xi’an Jiaotong University · Zhongguancun Academy, Beijing, China +2

Protein Structure Generation Generative Modeling 3D Molecular Generation Molecular Generation Diffusion Models

Apr 15, 2026

Polyformer: a generative framework for thermodynamic modeling of polymeric molecules

The classic paradigm of structural biology is that the sequence of a biomolecule (protein, nucleic acid, lipid, etc) determines its conformation (shape) which determines its biological function. Protein folding programs like AlphaFold address this paradigm by predicting the single best conformation given a sequence that defines the molecule. However, biomolecules are not static structures, and their conformational ensemble determines their function. We present the Polyformer -- a generative framework for thermodynamic modeling of polymeric molecules. Given the sequence and temperature (or another thermodynamic variable), the Polyformer generates conformations faithful to the molecule's thermodynamic conformational ensemble. It is the first generative model that solves three problems simultaneously: how does a molecule fold, what is its conformational ensemble, and how does the conformational ensemble change as we change physical temperature. As a concrete test case, we apply Polyformer to protein domains with 50-111 residues and report good agreement of model predictions to Molecular Dynamics (MD) trajectories.

Alessio Valentini, David Pekker, Chungwen Liang +2

PsiDagger, San Diego, CA · Department of Physics and Astronomy, University of Pittsburgh, Pittsburgh, PA · Department of Chemistry and The PULSE Institute, Stanford University, Stanford, CA +1

Protein Structure Generation Protein Structure Prediction Conditional Generative Modeling

Mar 17, 2026

PI-Mamba: Linear-Time Protein Backbone Generation via Spectrally Initialized Flow Matching

Motivation: Generative models for protein backbone design have to simultaneously ensure geometric validity, sampling efficiency, and scalability to long sequences. However, most existing approaches rely on iterative refinement, quadratic attention mechanisms, or post-hoc geometry correction, leading to a persistent trade-off between computational efficiency and structural fidelity. Results: We present Physics-Informed Mamba (PI-Mamba), a generative model that enforces exact local covalent geometry by construction while enabling linear-time inference. PI-Mamba integrates a differentiable constraint-enforcement operator into a flow-matching framework and couples it with a Mamba-based state-space architecture. To improve optimisation stability and backbone realism, we introduce a spectral initialization derived from the Rouse polymer model and an auxiliary cis-proline awareness head. Across benchmark tasks, PI-Mamba achieves 0.0% local geometry violations and high designability (scTM =

0.91\pm 0.03

, n = 100), while scaling to proteins exceeding 2,000 residues on a single A5000 GPU (24 GB).

Tianyu Wu, Lin Zhu

Center for Biophysics and Quantitative Biology, University of Illinois Urbana-Champaign, 600 S Mathews Ave., 61801, IL, USA · School of Information Science, University of Illinois Urbana-Champaign, 501 E Daniel St., 61820, IL, USA

Protein Structure Generation Protein Design Molecular Generation Constrained Generative Modeling Physics-Informed Generative Modeling Mamba+1

Mar 2, 2026

Rigidity-Aware Geometric Pretraining for Protein Design and Conformational Ensembles

Generative models have recently advanced

\textit{de novo}

protein design by learning the statistical regularities of natural structures. However, current approaches face three key limitations: (1) Existing methods cannot jointly learn protein geometry and design tasks, where pretraining can be a solution; (2) Current pretraining methods mostly rely on local, non-rigid atomic representations for property prediction downstream tasks, limiting global geometric understanding for protein generation tasks; and (3) Existing approaches have yet to effectively model the rich dynamic and conformational information of protein structures. To overcome these issues, we introduce

\textbf{RigidSSL}

(

\textit{Rigidity-Aware Self-Supervised Learning}

), a geometric pretraining framework that front-loads geometry learning prior to generative finetuning. Phase I (RigidSSL-Perturb) learns geometric priors from 432K structures from the AlphaFold Protein Structure Database with simulated perturbations. Phase II (RigidSSL-MD) refines these representations on 1.3K molecular dynamics trajectories to capture physically realistic transitions. Underpinning both phases is a bi-directional, rigidity-aware flow matching objective that jointly optimizes translational and rotational dynamics to maximize mutual information between conformations. Empirically, RigidSSL variants improve designability by up to 43% while enhancing novelty and diversity in unconditional generation. Furthermore, RigidSSL-Perturb improves the success rate by 5.8% in zero-shot motif scaffolding and RigidSSL-MD captures more biophysically realistic conformational ensembles in G protein-coupled receptor modeling.

Zhanghan Ni, Yanjing Li, Zeju Qiu +4

University of Illinois Urbana-Champaign · University of Washington · MPI for Intelligent Systems, Tübingen +3

Protein Structure Generation Generative Modeling Protein Design Self-Supervised Pre-Training Protein Representation Learning Geometric Representation Learning

Oct 3, 2025

SPID: Distilled Protein Backbone Generation

Diffusion- and flow-based generative models have recently demonstrated strong performance in protein backbone generation tasks, offering unprecedented capabilities for de novo protein design. However, despite their generation quality, these models are constrained by slow sampling, often requiring hundreds of iterative steps. This computational bottleneck limits their practical utility in large-scale protein discovery, where thousands to millions of candidate structures are needed. To address this challenge, we explore the techniques of score distillation, which has shown great success in reducing the number of sampling steps in the vision domain while maintaining high generation quality. However, a straightforward adaptation of these methods results in unacceptably low designability. We introduce Score Protein identity Distillation (SPID), which resolves this incompatibility by combining few-step generation with inference-time noise scaling. SPID adapts the Score identity Distillation (SiD) framework to both diffusion- and flow-based models without requiring access to pretraining data. Applied to the Proteina flow-matching model, our 16-step generator achieves 94.4% designability, matching the 400-step teacher, while delivering more than a 20-fold reduction in effective backbone-generation time and maintaining comparable diversity and novelty. SPID generalizes across unconditional generation, fold-class conditional generation, and motif scaffolding, and extends to equivariant diffusion architectures, achieving significant reduction in generation time with comparable generation quality to the teacher in all tasks. The resulting reduction in inference cost could facilitate large-scale in silico protein design, thereby advancing diffusion-based models toward real-world protein engineering applications. The PyTorch implementation is available at https://github.com/LY-Xie/SiD_Protein

Liyang Xie, Haoran Zhang, Zhendong Wang +2

The University of Texas at Austin · The Memorial Sloan Kettering Cancer Center

Diffusion Model Distillation Few-Step Diffusion Sampling Molecular Generation Protein Design Protein Structure Generation