Biomolecules such as proteins and small-molecule ligands play a central role in biological systems, arising from the tight interplay between sequence and three-dimensional structure. Recent generative models for biomolecular co-design aim to capture this interplay by jointly modeling coupled modalities. However, existing approaches largely adopt a parallel execution of marginal generative processes, implicitly enforcing fixed synchronous coupling. We argue that a critical but overlooked degree of freedom lies in how these marginal processes are temporally coupled during training and generation, where inappropriate coupling can introduce high-variance supervision and inconsistent intermediate states, affecting modality consistency. To address this, we introduce GeoCoupling, a systematic framework that optimizes for temporal couplings between heterogeneous modalities. Empirical results across structure-based drug design and unconditional protein design demonstrate the learned couplings consistently outperform synchronous and randomly coupled baselines, yielding biomolecules with improved physical validity and diversity.
Proteins are fundamental to biological processes, with their function determined by the complex interplay between the amino acid sequence and the three-dimensional structure. Developing generative models capable of understanding this intrinsically multi-modal relationship is crucial for fields like drug discovery and protein engineering. Existing models often rely on a multi-stage training process where autoencoders that tokenize data into latent representations are trained in a first stage. Secondly, a generative model is trained on the latent representation of the autoencoder(s), i.e., generative modeling in a latent space. We hypothesize that this multi-stage training is not necessary to obtain performant co-design models and thus present SimpleDesign, an effective multi-modal protein design model trained directly in the data space. SimpleDesign leverages a single-stage end-to-end objective that combines discrete cross-entropy for sequences and a regression objective for structures. In order to effectively model the difference in sequence and structure modalities, we develop a Mixture-of-Transformer architecture that allows modality-specific processing while keeping global self-attention over both modalities. We train SimpleDesign on over 2M sequence-structure pairs achieving strong performance across co-design and unconditional sequence/structure generation benchmarks.
The rapid evolution of generative models has unlocked new potentials in protein binder design, a pivotal task in structural biology, by facilitating end-to-end generation via joint sequence-structure modeling or hallucination. However, existing approaches are predominantly implemented under a single-target, single-state assumption, limiting their ability to model multi-target or multi-state interactions required for advanced function-oriented protein design. Here, we introduce Chamaileon, which unifies multi-target and multi-state binder design by formulating the problem as cross-context binding landscape modeling. The framework is underpinned by a training paradigm termed In-Context Complex Co-Design (I3CD) for context-aware sequence-structure co-modeling. During inference, we employ Mixture-of-Paths Sampling (MoPS), a scalable strategy that optimizes a single sequence across contexts while alleviating the scarcity of high-quality multi-conformational paired data. Extensive evaluation on our newly constructed benchmark, CROSS, demonstrates that Chamaileon effectively generates sequences adaptable to diverse conformational landscapes and multi-target requirements. The code is available on https://github.com/caohengyuan/Chamaileon.
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.