Molecule Generation with Fragment Retrieval Augmentation

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). f-RAG is based on a pre-trained molecular generative model that proposes additional fragments from input fragments to complete and generate a new molecule. Given a fragment vocabulary, f-RAG retrieves two types of fragments: (1) hard fragments, which serve as building blocks that will be explicitly included in the newly generated molecule, and (2) soft fragments, which serve as reference to guide the generation of new fragments through a trainable fragment injection module. To extrapolate beyond the existing fragments, f-RAG updates the fragment vocabulary with generated fragments via an iterative refinement process which is further enhanced with post-hoc genetic fragment modification. f-RAG can achieve an improved exploration-exploitation trade-off by maintaining a pool of fragments and expanding it with novel and high-quality fragments through a strong generative prior.

Multi-student Diffusion Distillation for Better One-step Generators

Diffusion models achieve high-quality sample generation at the cost of a lengthy multistep inference procedure. To overcome this, diffusion distillation techniques produce student generators capable of matching or surpassing the teacher in a single step. However, the student model's inference speed is limited by the size of the teacher architecture, preventing real-time generation for computationally heavy applications. In this work, we introduce Multi-Student Distillation (MSD), a framework to distill a conditional teacher diffusion model into multiple single-step generators. Each student generator is responsible for a subset of the conditioning data, thereby obtaining higher generation quality for the same capacity. MSD trains multiple distilled students, allowing smaller sizes and, therefore, faster inference. Also, MSD offers a lightweight quality boost over single-student distillation with the same architecture. We demonstrate MSD is effective by training multiple same-sized or smaller students on single-step distillation using distribution matching and adversarial distillation techniques. With smaller students, MSD gets competitive results with faster inference for single-step generation. Using 4 same-sized students, MSD sets a new state-of-the-art for one-step image generation: FID 1.20 on ImageNet-64x64 and 8.20 on zero-shot COCO2014.

Energy-Based Diffusion Language Models for Text Generation

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. In this work, we propose Energy-based Diffusion Language Model (EDLM), an energy-based model operating at the full sequence level for each diffusion step, introduced to improve the underlying approximation used by diffusion models. More specifically, we introduce an EBM in a residual form, and show that its parameters can be obtained by leveraging a pretrained autoregressive model or by finetuning a bidirectional transformer via noise contrastive estimation. We also propose an efficient generation algorithm via parallel important sampling. Comprehensive experiments on language modeling benchmarks show that our model can consistently outperform state-of-the-art diffusion models by a significant margin, and approaches autoregressive models' perplexity. We further show that, without any generation performance drop, our framework offers a 1.3$\times$ sampling speedup over existing diffusion models.

Warped Diffusion: Solving Video Inverse Problems with Image Diffusion Models

Using image models naively for solving inverse video problems often suffers from flickering, texture-sticking, and temporal inconsistency in generated videos. To tackle these problems, in this paper, we view frames as continuous functions in the 2D space, and videos as a sequence of continuous warping transformations between different frames. This perspective allows us to train function space diffusion models only on images and utilize them to solve temporally correlated inverse problems. The function space diffusion models need to be equivariant with respect to the underlying spatial transformations. To ensure temporal consistency, we introduce a simple post-hoc test-time guidance towards (self)-equivariant solutions. Our method allows us to deploy state-of-the-art latent diffusion models such as Stable Diffusion XL to solve video inverse problems. We demonstrate the effectiveness of our method for video inpainting and $8\times$ video super-resolution, outperforming existing techniques based on noise transformations. We provide generated video results: https://giannisdaras.github.io/warped\_diffusion.github.io/.

Truncated Consistency 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. We empirically find that this training paradigm limits the one-step generation performance of consistency models. To address this issue, we generalize consistency training to the truncated time range, which allows the model to ignore denoising tasks at earlier time steps and focus its capacity on generation. We propose a new parameterization of the consistency function and a two-stage training procedure that prevents the truncated-time training from collapsing to a trivial solution. Experiments on CIFAR-10 and ImageNet $64\times64$ datasets show that our method achieves better one-step and two-step FIDs than the state-of-the-art consistency models such as iCT-deep, using more than 2$\times$ smaller networks. Project page: https://truncated-cm.github.io/

EquiJump: Protein Dynamics Simulation via SO(3)-Equivariant Stochastic Interpolants

Mapping the conformational dynamics of proteins is crucial for elucidating their functional mechanisms. While Molecular Dynamics (MD) simulation enables detailed time evolution of protein motion, its computational toll hinders its use in practice. To address this challenge, multiple deep learning models for reproducing and accelerating MD have been proposed drawing on transport-based generative methods. However, existing work focuses on generation through transport of samples from prior distributions, that can often be distant from the data manifold. The recently proposed framework of stochastic interpolants, instead, enables transport between arbitrary distribution endpoints. Building upon this work, we introduce EquiJump, a transferable SO(3)-equivariant model that bridges all-atom protein dynamics simulation time steps directly. Our approach unifies diverse sampling methods and is benchmarked against existing models on trajectory data of fast folding proteins. EquiJump achieves state-of-the-art results on dynamics simulation with a transferable model on all of the fast folding proteins.

DisCo-Diff: Enhancing Continuous Diffusion Models with Discrete Latents

Diffusion models (DMs) have revolutionized generative learning. They utilize a diffusion process to encode data into a simple Gaussian distribution. However, encoding a complex, potentially multimodal data distribution into a single continuous Gaussian distribution arguably represents an unnecessarily challenging learning problem. We propose Discrete-Continuous Latent Variable Diffusion Models (DisCo-Diff) to simplify this task by introducing complementary discrete latent variables. We augment DMs with learnable discrete latents, inferred with an encoder, and train DM and encoder end-to-end. DisCo-Diff does not rely on pre-trained networks, making the framework universally applicable. The discrete latents significantly simplify learning the DM's complex noise-to-data mapping by reducing the curvature of the DM's generative ODE. An additional autoregressive transformer models the distribution of the discrete latents, a simple step because DisCo-Diff requires only few discrete variables with small codebooks. We validate DisCo-Diff on toy data, several image synthesis tasks as well as molecular docking, and find that introducing discrete latents consistently improves model performance. For example, DisCo-Diff achieves state-of-the-art FID scores on class-conditioned ImageNet-64/128 datasets with ODE sampler.

Aligning Target-Aware Molecule Diffusion Models with Exact Energy Optimization

Generating ligand molecules for specific protein targets, known as structure-based drug design, is a fundamental problem in therapeutics development and biological discovery. Recently, target-aware generative models, especially diffusion models, have shown great promise in modeling protein-ligand interactions and generating candidate drugs. However, existing models primarily focus on learning the chemical distribution of all drug candidates, which lacks effective steerability on the chemical quality of model generations. In this paper, we propose a novel and general alignment framework to align pretrained target diffusion models with preferred functional properties, named AliDiff. AliDiff shifts the target-conditioned chemical distribution towards regions with higher binding affinity and structural rationality, specified by user-defined reward functions, via the preference optimization approach. To avoid the overfitting problem in common preference optimization objectives, we further develop an improved Exact Energy Preference Optimization method to yield an exact and efficient alignment of the diffusion models, and provide the closed-form expression for the converged distribution. Empirical studies on the CrossDocked2020 benchmark show that AliDiff can generate molecules with state-of-the-art binding energies with up to -7.07 Avg. Vina Score, while maintaining strong molecular properties.

L4GM: Large 4D Gaussian Reconstruction Model

We present L4GM, the first 4D Large Reconstruction Model that produces animated objects from a single-view video input -- in a single feed-forward pass that takes only a second. Key to our success is a novel dataset of multiview videos containing curated, rendered animated objects from Objaverse. This dataset depicts 44K diverse objects with 110K animations rendered in 48 viewpoints, resulting in 12M videos with a total of 300M frames. We keep our L4GM simple for scalability and build directly on top of LGM, a pretrained 3D Large Reconstruction Model that outputs 3D Gaussian ellipsoids from multiview image input. L4GM outputs a per-frame 3D Gaussian Splatting representation from video frames sampled at a low fps and then upsamples the representation to a higher fps to achieve temporal smoothness. We add temporal self-attention layers to the base LGM to help it learn consistency across time, and utilize a per-timestep multiview rendering loss to train the model. The representation is upsampled to a higher framerate by training an interpolation model which produces intermediate 3D Gaussian representations. We showcase that L4GM that is only trained on synthetic data generalizes extremely well on in-the-wild videos, producing high quality animated 3D assets.

Outdoor Scene Extrapolation with Hierarchical Generative Cellular Automata

We aim to generate fine-grained 3D geometry from large-scale sparse LiDAR scans, abundantly captured by autonomous vehicles (AV). Contrary to prior work on AV scene completion, we aim to extrapolate fine geometry from unlabeled and beyond spatial limits of LiDAR scans, taking a step towards generating realistic, high-resolution simulation-ready 3D street environments. We propose hierarchical Generative Cellular Automata (hGCA), a spatially scalable conditional 3D generative model, which grows geometry recursively with local kernels following, in a coarse-to-fine manner, equipped with a light-weight planner to induce global consistency. Experiments on synthetic scenes show that hGCA generates plausible scene geometry with higher fidelity and completeness compared to state-of-the-art baselines. Our model generalizes strongly from sim-to-real, qualitatively outperforming baselines on the Waymo-open dataset. We also show anecdotal evidence of the ability to create novel objects from real-world geometric cues even when trained on limited synthetic content. More results and details can be found on https://research.nvidia.com/labs/toronto-ai/hGCA/.