Tomas Geffner

Siyi Gu, Minkai Xu, Alexander Powers et al.

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. Code is available at https://github.com/MinkaiXu/AliDiff.

Tomas Geffner, George Papamakarios, Andriy Mnih

Neural Posterior Estimation methods for simulation-based inference can be ill-suited for dealing with posterior distributions obtained by conditioning on multiple observations, as they tend to require a large number of simulator calls to learn accurate approximations. In contrast, Neural Likelihood Estimation methods can handle multiple observations at inference time after learning from individual observations, but they rely on standard inference methods, such as MCMC or variational inference, which come with certain performance drawbacks. We introduce a new method based on conditional score modeling that enjoys the benefits of both approaches. We model the scores of the (diffused) posterior distributions induced by individual observations, and introduce a way of combining the learned scores to approximately sample from the target posterior distribution. Our approach is sample-efficient, can naturally aggregate multiple observations at inference time, and avoids the drawbacks of standard inference methods.

Kieran Didi, Zuobai Zhang, Guoqing Zhou et al.

Protein interaction modeling is central to protein design, which has been transformed by machine learning with applications in drug discovery and beyond. In this landscape, structure-based de novo binder design is cast as either conditional generative modeling or sequence optimization via structure predictors ("hallucination"). We argue that this is a false dichotomy and propose Proteina-Complexa, a novel fully atomistic binder generation method unifying both paradigms. We extend recent flow-based latent protein generation architectures and leverage the domain-domain interactions of monomeric computationally predicted protein structures to construct Teddymer, a new large-scale dataset of synthetic binder-target pairs for pretraining. Combined with high-quality experimental multimers, this enables training a strong base model. We then perform inference-time optimization with this generative prior, unifying the strengths of previously distinct generative and hallucination methods. Proteina-Complexa sets a new state of the art in computational binder design benchmarks: it delivers markedly higher in-silico success rates than existing generative approaches, and our novel test-time optimization strategies greatly outperform previous hallucination methods under normalized compute budgets. We also demonstrate interface hydrogen bond optimization, fold class-guided binder generation, and extensions to small molecule targets and enzyme design tasks, again surpassing prior methods. Code, models and new data will be publicly released.

Tomas Geffner, Justin Domke

Many methods that build powerful variational distributions based on unadjusted Langevin transitions exist. Most of these were developed using a wide range of different approaches and techniques. Unfortunately, the lack of a unified analysis and derivation makes developing new methods and reasoning about existing ones a challenging task. We address this giving a single analysis that unifies and generalizes these existing techniques. The main idea is to augment the target and variational by numerically simulating the underdamped Langevin diffusion process and its time reversal. The benefits of this approach are twofold: it provides a unified formulation for many existing methods, and it simplifies the development of new ones. In fact, using our formulation we propose a new method that combines the strengths of previously existing algorithms; it uses underdamped Langevin transitions and powerful augmentations parameterized by a score network. Our empirical evaluation shows that our proposed method consistently outperforms relevant baselines in a wide range of tasks.

Tomas Geffner, Justin Domke

Hierarchical models represent a challenging setting for inference algorithms. MCMC methods struggle to scale to large models with many local variables and observations, and variational inference (VI) may fail to provide accurate approximations due to the use of simple variational families. Some variational methods (e.g. importance weighted VI) integrate Monte Carlo methods to give better accuracy, but these tend to be unsuitable for hierarchical models, as they do not allow for subsampling and their performance tends to degrade for high dimensional models. We propose a new family of variational bounds for hierarchical models, based on the application of tightening methods (e.g. importance weighting) separately for each group of local random variables. We show that our approach naturally allows the use of subsampling to get unbiased gradients, and that it fully leverages the power of methods that build tighter lower bounds by applying them independently in lower dimensional spaces, leading to better results and more accurate posterior approximations than relevant baselines.

Jean-Marie Lemercier, Tomas Geffner, Karsten Kreis et al.

Diffusion language models intrinsically fail to capture correlations between decoded tokens, which leads to a harsh trade-off between sampling quality and throughput. To solve this issue, we propose DiLaDiff, a variant of masked diffusion language models with three components: (1) a continuous latent space with semantic capabilities, learned by an auto-encoder fine-tuned from an existing masked diffusion language model; (2) a latent diffusion model learning the prior over the encoder distribution; (3) a consistency model distilling the learned prior into a few-step latent generative model. We show that, even without distillation, our latent-guided diffusion model outperforms the masked diffusion baseline while significantly accelerating inference. Consistency distillation further lowers the computational overhead of continuous diffusion, such that the latent is generated in negligible time compared to discrete decoding.

Minkai Xu, Tomas Geffner, Karsten Kreis et al.

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. Reproduced code is available at https://github.com/MinkaiXu/Energy-Diffusion-LLM.

Xi Wang, Tomas Geffner, Justin Domke

Black-box variational inference performance is sometimes hindered by the use of gradient estimators with high variance. This variance comes from two sources of randomness: Data subsampling and Monte Carlo sampling. While existing control variates only address Monte Carlo noise, and incremental gradient methods typically only address data subsampling, we propose a new "joint" control variate that jointly reduces variance from both sources of noise. This significantly reduces gradient variance, leading to faster optimization in several applications.

Joohwan Ko, Tomas Geffner

Denoising score matching (DSM) for training diffusion models may suffer from high variance at low noise levels. Target Score Matching (TSM) mitigates this when clean data scores are available, providing a low-variance objective. In many applications clean scores are inaccessible due to the presence of latent variables, leaving only joint signals exposed. We propose Latent Target Score Matching (LTSM), an extension of TSM to leverage joint scores for low-variance supervision of the marginal score. While LTSM is effective at low noise levels, a mixture with DSM ensures robustness across noise scales. Across simulation-based inference tasks, LTSM consistently improves variance, score accuracy, and sample quality.

Tomas Geffner, Kieran Didi, Zuobai Zhang et al.

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 further explore scaling training data to millions of synthetic protein structures and explore improved training and sampling recipes adapted to protein backbone generation. This includes fine-tuning strategies like LoRA for protein backbones, new guidance methods like classifier-free guidance and autoguidance for protein backbones, and new adjusted training objectives. Proteina achieves state-of-the-art performance on de novo protein backbone design and produces diverse and designable proteins at unprecedented length, up to 800 residues. The hierarchical conditioning offers novel control, enabling high-level secondary-structure guidance as well as low-level fold-specific generation.

Tomas Geffner, Kieran Didi, Zhonglin Cao et al.

Recently, many generative models for de novo protein structure design have emerged. Yet, only few tackle the difficult task of directly generating fully atomistic structures jointly with the underlying amino acid sequence. This is challenging, for instance, because the model must reason over side chains that change in length during generation. We introduce La-Proteina for atomistic protein design based on a novel partially latent protein representation: coarse backbone structure is modeled explicitly, while sequence and atomistic details are captured via per-residue latent variables of fixed dimensionality, thereby effectively side-stepping challenges of explicit side-chain representations. Flow matching in this partially latent space then models the joint distribution over sequences and full-atom structures. La-Proteina achieves state-of-the-art performance on multiple generation benchmarks, including all-atom co-designability, diversity, and structural validity, as confirmed through detailed structural analyses and evaluations. Notably, La-Proteina also surpasses previous models in atomistic motif scaffolding performance, unlocking critical atomistic structure-conditioned protein design tasks. Moreover, La-Proteina is able to generate co-designable proteins of up to 800 residues, a regime where most baselines collapse and fail to produce valid samples, demonstrating La-Proteina's scalability and robustness.

Sangyun Lee, Yilun Xu, Tomas Geffner et al.

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/

Stathi Fotiadis, Noah Brenowitz, Tomas Geffner et al.

Conditioning diffusion and flow models have proven effective for super-resolving small-scale details in natural images.However, in physical sciences such as weather, super-resolving small-scale details poses significant challenges due to: (i) misalignment between input and output distributions (i.e., solutions to distinct partial differential equations (PDEs) follow different trajectories), (ii) multi-scale dynamics, deterministic dynamics at large scales vs. stochastic at small scales, and (iii) limited data, increasing the risk of overfitting. To address these challenges, we propose encoding the inputs to a latent base distribution that is closer to the target distribution, followed by flow matching to generate small-scale physics. The encoder captures the deterministic components, while flow matching adds stochastic small-scale details. To account for uncertainty in the deterministic part, we inject noise into the encoder output using an adaptive noise scaling mechanism, which is dynamically adjusted based on maximum-likelihood estimates of the encoder predictions. We conduct extensive experiments on both the real-world CWA weather dataset and the PDE-based Kolmogorov dataset, with the CWA task involving super-resolving the weather variables for the region of Taiwan from 25 km to 2 km scales. Our results show that the proposed stochastic flow matching (SFM) framework significantly outperforms existing methods such as conditional diffusion and flows.

Zhonglin Cao, Mario Geiger, Allan dos Santos Costa et al.

Fast and accurate generation of molecular conformers is desired for downstream computational chemistry and drug discovery tasks. Currently, training and sampling state-of-the-art diffusion or flow-based models for conformer generation require significant computational resources. In this work, we build upon flow-matching and propose two mechanisms for accelerating training and inference of generative models for 3D molecular conformer generation. For fast training, we introduce the SO(3)-Averaged Flow training objective, which leads to faster convergence to better generation quality compared to conditional optimal transport flow or Kabsch-aligned flow. We demonstrate that models trained using SO(3)-Averaged Flow can reach state-of-the-art conformer generation quality. For fast inference, we show that the reflow and distillation methods of flow-based models enable few-steps or even one-step molecular conformer generation with high quality. The training techniques proposed in this work show a path towards highly efficient molecular conformer generation with flow-based models.

Shiv Shankar, Tomas Geffner

Flow matching models typically use linear interpolants to define the forward/noise addition process. This, together with the independent coupling between noise and target distributions, yields a vector field which is often non-straight. Such curved fields lead to a slow inference/generation process. In this work, we propose to learn flexible (potentially curved) interpolants in order to learn straight vector fields to enable faster generation. We formulate this via a multi-level optimization problem and propose an efficient approximate procedure to solve it. Our framework provides an end-to-end and simulation-free optimization procedure, which can be leveraged to learn straight line generative trajectories.

Tomas Geffner, Javier Antoran, Adam Foster et al.

Causal inference is essential for data-driven decision making across domains such as business engagement, medical treatment and policy making. However, research on causal discovery has evolved separately from inference methods, preventing straight-forward combination of methods from both fields. In this work, we develop Deep End-to-end Causal Inference (DECI), a single flow-based non-linear additive noise model that takes in observational data and can perform both causal discovery and inference, including conditional average treatment effect (CATE) estimation. We provide a theoretical guarantee that DECI can recover the ground truth causal graph under standard causal discovery assumptions. Motivated by application impact, we extend this model to heterogeneous, mixed-type data with missing values, allowing for both continuous and discrete treatment decisions. Our results show the competitive performance of DECI when compared to relevant baselines for both causal discovery and (C)ATE estimation in over a thousand experiments on both synthetic datasets and causal machine learning benchmarks across data-types and levels of missingness.

Tomas Geffner, Justin Domke

Given an unnormalized target distribution we want to obtain approximate samples from it and a tight lower bound on its (log) normalization constant log Z. Annealed Importance Sampling (AIS) with Hamiltonian MCMC is a powerful method that can be used to do this. Its main drawback is that it uses non-differentiable transition kernels, which makes tuning its many parameters hard. We propose a framework to use an AIS-like procedure with Uncorrected Hamiltonian MCMC, called Uncorrected Hamiltonian Annealing. Our method leads to tight and differentiable lower bounds on log Z. We show empirically that our method yields better performances than other competing approaches, and that the ability to tune its parameters using reparameterization gradients may lead to large performance improvements.

Tomas Geffner, Justin Domke

In this paper we empirically evaluate biased methods for alpha-divergence minimization. In particular, we focus on how the bias affects the final solutions found, and how this depends on the dimensionality of the problem. We find that (i) solutions returned by these methods appear to be strongly biased towards minimizers of the traditional "exclusive" KL-divergence, KL(q||p), and (ii) in high dimensions, an impractically large amount of computation is needed to mitigate this bias and obtain solutions that actually minimize the alpha-divergence of interest.

Tomas Geffner, Justin Domke

Several approximate inference algorithms have been proposed to minimize an alpha-divergence between an approximating distribution and a target distribution. Many of these algorithms introduce bias, the magnitude of which becomes problematic in high dimensions. Other algorithms are unbiased. These often seem to suffer from high variance, but little is rigorously known. In this work we study unbiased methods for alpha-divergence minimization through the Signal-to-Noise Ratio (SNR) of the gradient estimator. We study several representative scenarios where strong analytical results are possible, such as fully-factorized or Gaussian distributions. We find that when alpha is not zero, the SNR worsens exponentially in the dimensionality of the problem. This casts doubt on the practicality of these methods. We empirically confirm these theoretical results.

Tomas Geffner, Justin Domke

Flexible variational distributions improve variational inference but are harder to optimize. In this work we present a control variate that is applicable for any reparameterizable distribution with known mean and covariance matrix, e.g. Gaussians with any covariance structure. The control variate is based on a quadratic approximation of the model, and its parameters are set using a double-descent scheme by minimizing the gradient estimator's variance. We empirically show that this control variate leads to large improvements in gradient variance and optimization convergence for inference with non-factorized variational distributions.

Tomas Geffner, Justin Domke

Stochastic gradient descent (SGD) is the workhorse of modern machine learning. Sometimes, there are many different potential gradient estimators that can be used. When so, choosing the one with the best tradeoff between cost and variance is important. This paper analyzes the convergence rates of SGD as a function of time, rather than iterations. This results in a simple rule to select the estimator that leads to the best optimization convergence guarantee. This choice is the same for different variants of SGD, and with different assumptions about the objective (e.g. convexity or smoothness). Inspired by this principle, we propose a technique to automatically select an estimator when a finite pool of estimators is given. Then, we extend to infinite pools of estimators, where each one is indexed by control variate weights. This is enabled by a reduction to a mixed-integer quadratic program. Empirically, automatically choosing an estimator performs comparably to the best estimator chosen with hindsight.

Tomas Geffner, Justin Domke

Variational inference is increasingly being addressed with stochastic optimization. In this setting, the gradient's variance plays a crucial role in the optimization procedure, since high variance gradients lead to poor convergence. A popular approach used to reduce gradient's variance involves the use of control variates. Despite the good results obtained, control variates developed for variational inference are typically looked at in isolation. In this paper we clarify the large number of control variates that are available by giving a systematic view of how they are derived. We also present a Bayesian risk minimization framework in which the quality of a procedure for combining control variates is quantified by its effect on optimization convergence rates, which leads to a very simple combination rule. Results show that combining a large number of control variates this way significantly improves the convergence of inference over using the typical gradient estimators or a reduced number of control variates.

Tomas Geffner, Hector Geffner

Fully observable non-deterministic (FOND) planning is becoming increasingly important as an approach for computing proper policies in probabilistic planning, extended temporal plans in LTL planning, and general plans in generalized planning. In this work, we introduce a SAT encoding for FOND planning that is compact and can produce compact strong cyclic policies. Simple variations of the encodings are also introduced for strong planning and for what we call, dual FOND planning, where some non-deterministic actions are assumed to be fair (e.g., probabilistic) and others unfair (e.g., adversarial). The resulting FOND planners are compared empirically with existing planners over existing and new benchmarks. The notion of "probabilistic interesting problems" is also revisited to yield a more comprehensive picture of the strengths and limitations of current FOND planners and the proposed SAT approach.