protein design engineers

Abstract: Few-step generative models produce high-quality samples in one or a few evaluations. However, steering them toward desired properties remains difficult, especially when only black-box reward evaluations are available. While one could apply approaches developed for iterative diffusion and flow-based models, such as direct RL fine-tuning or test-time scaling, we find that neither transfers well to the few-step regime: direct fine-tuning suffers from severe reward over-optimization, and test-time scaling sacrifices the efficiency advantage of few-step generation. We propose Noise Policy Optimization (NPO), which explicitly targets the alignment problem for few-step generative models. The key idea is to learn an amortized flow policy over the initial noise space of the generator. The trained policy transports Gaussian noise to a reward-tilted noise distribution, whose pushforward distribution through the frozen generator is exactly the reward-tilted output distribution. By keeping the generator frozen, we can effectively utilize the knowledge encoded in the pretrained model, yielding a better reward-quality trade-off than direct fine-tuning. The amortized policy moves the search cost into training, so inference adds only a lightweight noise sampling step on top of the pretrained model. To improve sample efficiency during training, we use ELBO-based likelihood estimation that requires only sampled endpoints rather than simulated trajectories. Across image, language, and protein structure generation, NPO consistently achieves a better reward-quality trade-off than direct fine-tuning, and matches test-time search methods with 16 to 549 times lower inference cost.

Abstract: We show that continuous bitstream diffusion (CoBit), originally developed for language modeling, provides a unified framework for joint and conditional multimodal generation using the same training and sampling protocol. Across image-text, speech-text and protein sequence-structure modeling, models are trained separately from scratch, but each uses a single input projection, transformer backbone, bitwise prediction head and binary score-matching objective shared across its modalities. Within each setting, a single checkpoint supports joint generation and the conditional directions included in training by changing which parts of the bitstream are observed. We first validate the approach on MNIST-Sum, a controlled image-text task pairing raw binary images with equations encoded as text, achieving near-perfect conditional accuracy and high joint consistency without learned tokenizers. We then apply the same protocol at larger scale to speech-text and protein sequence-structure modeling. Trained without text pretraining, a single speech-text model performs speech synthesis, recognition, continuation, and unconditional co-generation. Jointly generated speech and text achieve 3.5% word error rate between the generated text and automatic transcriptions of the generated speech. In protein modeling, a single CoBit checkpoint supports forward folding, inverse folding, and joint sequence-structure generation. For jointly generated proteins spanning 100-500 residues, computational refolding of CoBit's sequences yields structures that agree with the generated backbones at a mean self-consistency TM-score of 0.911. Together, these results show that CoBit provides a common generative framework for substantially different modalities and forms of cross-modal dependence, without introducing a domain-specific objective or sampling procedure.

Abstract: Generative models are often trained with isotropic objectives such as mean-squared error. For data concentrated near a low-dimensional manifold, however, such losses conflate displacement along the manifold, which may represent valid variation, with displacement away from it, which produces invalid samples. This mismatch is especially problematic in sparse, highly constrained domains, where ambient-space regression can encourage off-manifold interpolation. We ask whether a generative objective can distinguish manifold-parallel variation from manifold-orthogonal deviation directly from data, without explicitly estimating the manifold. We introduce a manifold-decomposed feature loss (MaDeL) that learns complementary representations from corrupted observations: one is trained to recover the clean sample, while the other is trained to recover the corruption. We show that, under a feature bottleneck, their Jacobians align with the tangent and normal spaces, exactly for linear manifolds and locally for smooth manifolds. Together, these representations define an anisotropic objective that separately measures intrinsic variation and off-manifold deviation. Across synthetic, Earth and climate science, and torsion-angle benchmarks, MaDeL improves support recovery and average angular $W_1$ under single-step sampling; on protein backbones, it reduces steric clashes across one- and few-step sampling budgets.