Calibrating Generative Models to Feature Distributions with MMD Finetuning

Generative models can produce individually plausible samples while deviating substantially from a target set in the distribution of key features. For example, a model pretrained on broad drug-like chemical space may generate molecules whose molecular features differ from those of a therapeutic class of interest, such as known antibiotics. Correcting such distributional miscalibration is challenging: direct finetuning on the target set can overfit and does not control which features are matched. To fill this gap, we introduce kernel Calibrating Generative Models (kCGM). kCGM minimizes a maximum mean discrepancy (MMD) between generated and target feature distributions using an unbiased score-function estimator, with KL regularization to remain close to the pretrained model. On a target set of 174 antibiotics, direct finetuning sacrifices chemical validity for feature-distribution matching, whereas kCGM improves target feature matching while increasing validity. We further demonstrate kCGM in protein and DNA generation tasks, showing it can adapt autoregressive, continuous-space diffusion, and discrete diffusion models using only feature-level supervision. Code is available at https://github.com/smithhenryd/cgm.

Flexible Flows for Biological Sequence Design

Designing functional biological sequences requires navigating vast discrete spaces under strict evolutionary and biophysical constraints. Discrete Flow Matching (DFM) offers a generative framework over such spaces, but existing approaches rely on biologically uninformative couplings and offer limited flexibility for variable-length sequence generation and fine-grained control. We propose a structured coupling that encodes domain-specific preferences among sequence elements, biasing the source distribution toward plausible regions without modifying the flow objective or training procedure. Building on this, we introduce a latent edit-based rate parameterization that models variable-length generation via edit operations conditioned on a shared global latent, akin to a latent variable model, while remaining tractable. We further introduce a latent classifier-free guidance mechanism that steers generation coherently in continuous latent space, along with Dirichlet-prior temperature scaling for test-time control over edit operations. Our method achieves state-of-the-art performance across diverse biological sequence tasks, including density estimation, unconditional and conditional DNA sequence generation, and peptide sequence generation.

Plug-and-Play Guidance for Discrete Diffusion Models via Gradient-Informed Logit Correction

Controllable generation with discrete diffusion models is often hindered by high computational overhead or the need for retraining. In this paper, we present \underline{\textbf{G}}radient-\underline{\textbf{I}}nformed \underline{\textbf{L}}ogit \underline{\textbf{C}}orrection (\textbf{GILC}), a plug-and-play framework that efficiently estimates guidance signals by repurposing the pretrained denoising network as a variational proxy. To circumvent the gradient instability inherent in high-dimensional discrete spaces, we introduce a Jacobian-free mechanism that directly corrects the clean prediction logits, facilitating stable and effective guidance. Our method accommodates both differentiable and non-differentiable reward functions. Extensive experiments across DNA, protein sequence, and molecular generation tasks demonstrate that GILC achieves state-of-the-art performance without additional training, frequently outperforming fine-tuning approaches.