# Unlocking hidden biomolecular conformational landscapes in diffusion models at inference time

arXiv: https://arxiv.org/abs/2512.03312 · HTML: https://mlsanity.com/paper/2512.03312/

## Key facts

- Cited by 7 papers in the map (data through 14 Oct 2026).
- Placed in Flow matching, time series and science, one of 14 directions in Diffusion models.
- Builds on 7 of its 44 references that are in the map.
- First posted on arXiv 2 Dec 2025.

## Placed in

- Diffusion models / [Flow matching, time series and science](https://mlsanity.com/diffusion/flow-matching-time-series-and-science/)

## Builds on (most cited first, 7 of 7)

- [Diffusion Models Beat GANs on Image Synthesis](https://mlsanity.com/paper/2105.05233/) (2021)
- [Classifier-Free Diffusion Guidance](https://mlsanity.com/paper/2207.12598/) (2022)
- [Practical and Asymptotically Exact Conditional Sampling in Diffusion Models](https://mlsanity.com/paper/2306.17775/) (2023)
- [AlphaFold Meets Flow Matching for Generating Protein Ensembles](https://mlsanity.com/paper/2402.04845/) (2024)
- [Protein Conformation Generation via Force-Guided SE(3) Diffusion Models](https://mlsanity.com/paper/2403.14088/) (2024)
- [Str2Str: A Score-based Framework for Zero-shot Protein Conformation Sampling](https://mlsanity.com/paper/2306.03117/) (2023)
- [Solving Inverse Problems in Protein Space Using Diffusion-Based Priors](https://mlsanity.com/paper/2406.04239/) (2024)

## Built on by (most cited first, 7 of 7)

- [Enhanced Diffusion Sampling: Efficient Rare Event Sampling and Free Energy Calculation with Diffusion Models](https://mlsanity.com/paper/2602.16634/) (2026)
- [Robust Inference-Time Steering of Protein Diffusion Models via Embedding Optimization](https://mlsanity.com/paper/2602.05285/) (2026)
- [Inference-time optimization for experiment-grounded protein ensemble generation](https://mlsanity.com/paper/2602.24007/) (2026)
- [METALICA: METAdynamics and repLICA exchange for enhanced diffusion sampling](https://mlsanity.com/paper/2609.17823/) (2026)
- [ConforNets: Latents-Based Conformational Control in OpenFold3](https://mlsanity.com/paper/2604.18559/) (2026)
- [Modeling Atomic Conformational Ensembles of Proteins via Test-Time Supervision of Boltz-2 on Cryo-EM Density Maps](https://mlsanity.com/paper/2605.09832/) (2026)
- [Learning Implicit Bias in Generative Spaces for Accelerating Protein Dynamics Emulation](https://mlsanity.com/paper/2606.01833/) (2026)

## Abstract (arXiv)

The function of biomolecules such as proteins depends on their ability to interconvert between a wide range of structures or "conformations." Researchers have endeavored for decades to develop computational methods to predict the distribution of conformations, which is far harder to determine experimentally than a static folded structure. We present ConforMix, an inference-time algorithm that enhances sampling of conformational distributions using a combination of classifier guidance, filtering, and free energy estimation. Our approach upgrades diffusion models -- whether trained for static structure prediction or conformational generation -- to enable more efficient discovery of conformational variability without requiring prior knowledge of major degrees of freedom. ConforMix is orthogonal to improvements in model pretraining and would benefit even a hypothetical model that perfectly reproduced the Boltzmann distribution. Remarkably, when applied to a diffusion model trained for static structure prediction, ConforMix captures structural changes including domain motion, cryptic pocket flexibility, and transporter cycling, while avoiding unphysical states. Case studies of biologically critical proteins demonstrate the scalability, accuracy, and utility of this method.