Recently, diffusion- and flow-based generative models of protein structures have emerged as a powerful tool for de novo protein design. Here, we develop Proteina, a new large-scale flow-based protein backbone generator that utilizes hierarchical fold class labels for conditioning and relies on a tailored scalable transformer architecture with up to 5x as many parameters as previous models. To meaningfully quantify performance, we introduce a new set of metrics that directly measure the distributional similarity of generated proteins with reference sets, complementing existing metrics.

We develop ProtComposer to generate protein structures conditioned on spatial protein layouts that are specified via a set of 3D ellipsoids capturing substructure shapes and semantics. At inference time, we condition on ellipsoids that are hand-constructed, extracted from existing proteins, or from a statistical model, with each option unlocking new capabilities. Hand-specifying ellipsoids enables users to control the location, size, orientation, secondary structure, and approximate shape of protein substructures.

Despite remarkable progress in autoregressive language models, alternative generative paradigms beyond left-to-right generation are still being actively explored. Discrete diffusion models, with the capacity for parallel generation, have recently emerged as a promising alternative. Unfortunately, these models still underperform the autoregressive counterparts, with the performance gap increasing when reducing the number of sampling steps. Our analysis reveals that this degradation is a consequence of an imperfect approximation used by diffusion models.

Consistency models have recently been introduced to accelerate sampling from diffusion models by directly predicting the solution (i.e., data) of the probability flow ODE (PF ODE) from initial noise. However, the training of consistency models requires learning to map all intermediate points along PF ODE trajectories to their corresponding endpoints. This task is much more challenging than the ultimate objective of one-step generation, which only concerns the PF ODE’s noise-to-data mapping.

Existing work on graph generation has, so far, mainly focused on undirected graphs. In this paper we propose a denoising autoencoder-based generative model that exploits the global structure of directed graphs (also called digraphs) via their Laplacian dynamics and enables one-shot generation.  Our noising encoder uses closed-form expressions based on the heat equation to corrupt its digraph input with uniform noise. Our decoder reconstructs the corrupted representation by exploiting the global topological information of the graph included in its random walk Laplacian matrix.

Fragment-based drug discovery, in which molecular fragments are assembled into new molecules with desirable biochemical properties, has achieved great success. However, many fragment-based molecule generation methods show limited exploration beyond the existing fragments in the database as they only reassemble or slightly modify the given ones. To tackle this problem, we propose a new fragment-based molecule generation framework with retrieval augmentation, namely Fragment Retrieval-Augmented Generation (f-RAG).