# Enhancing Diffusion-Based Sampling with Molecular Collective Variables

arXiv: https://arxiv.org/abs/2510.11923 · HTML: https://mlsanity.com/paper/2510.11923/

## Key facts

- Cited by 9 papers in the map (data through 14 Oct 2026).
- First posted on arXiv 13 Oct 2025.

## Built on by (most cited first, 9 of 9)

- [Enhanced Diffusion Sampling: Efficient Rare Event Sampling and Free Energy Calculation with Diffusion Models](https://mlsanity.com/paper/2602.16634/) (2026)
- [Bridge Matching Sampler: Scalable Sampling via Generalized Fixed-Point Diffusion Matching](https://mlsanity.com/paper/2603.00530/) (2026)
- [Learning Boltzmann Generators via Constrained Mass Transport](https://mlsanity.com/paper/2510.18460/) (2025)
- [Flow Sampling: Learning to Sample from Unnormalized Densities via Denoising Conditional Processes](https://mlsanity.com/paper/2605.03984/) (2026)
- [Few-Step Boltzmann Generators via Scalable Likelihood Flow Maps](https://mlsanity.com/paper/2606.29110/) (2026)
- [Learning Structure, Energy, and Dynamics: A Survey of Artificial Intelligence for Protein Dynamics](https://mlsanity.com/paper/2604.25244/) (2026)
- [Coarse-Grained Boltzmann Generators](https://mlsanity.com/paper/2602.10637/) (2026)
- [A Priori Sampling of Transition States with Guided Diffusion](https://mlsanity.com/paper/2603.25980/) (2026)
- [Learning Implicit Bias in Generative Spaces for Accelerating Protein Dynamics Emulation](https://mlsanity.com/paper/2606.01833/) (2026)

## Abstract (arXiv)

Diffusion-based samplers learn to sample complex, high-dimensional distributions using energies or log densities alone, without training data. Yet, they remain impractical for molecular sampling because they are often slower than molecular dynamics and miss thermodynamically relevant modes. Inspired by enhanced sampling, we encourage exploration by introducing a sequential bias along bespoke, information-rich, low-dimensional projections of atomic coordinates known as collective variables (CVs). We introduce a repulsive potential centered on the CVs from recent samples, which pushes future samples towards novel CV regions and effectively increases the temperature in the projected space. Our resulting method improves efficiency, mode discovery, enables the estimation of free energy differences, and retains independent sampling from the approximate Boltzmann distribution via reweighting by the bias. On standard peptide conformational sampling benchmarks, the method recovers diverse conformational states and accurate free energy profiles. We are the first to demonstrate reactive sampling using a diffusion-based sampler, capturing bond breaking and formation with universal interatomic potentials at near-first-principles accuracy. The approach resolves reactive energy landscapes at a fraction of the wall-clock time of standard sampling methods, advancing diffusion-based sampling towards practical use in molecular sciences.