# Aligning Protein Conformation Ensemble Generation with Physical Feedback

arXiv: https://arxiv.org/abs/2505.24203 · HTML: https://mlsanity.com/paper/2505.24203/

## Key facts

- Cited by 5 papers in the map (data through 14 Oct 2026).
- Builds on 26 of its 47 references that are in the map.
- First posted on arXiv 30 May 2025.

## Builds on (most cited first, 26 of 26)

- [Denoising Diffusion Probabilistic Models](https://mlsanity.com/paper/2006.11239/) (2020)
- [High-Resolution Image Synthesis with Latent Diffusion Models](https://mlsanity.com/paper/2112.10752/) (2021)
- [Training language models to follow instructions with human feedback](https://mlsanity.com/paper/2203.02155/) (2022)
- [Denoising Diffusion Implicit Models](https://mlsanity.com/paper/2010.02502/) (2020)
- [Direct Preference Optimization: Your Language Model is Secretly a Reward Model](https://mlsanity.com/paper/2305.18290/) (2023)
- [Deep Unsupervised Learning using Nonequilibrium Thermodynamics](https://mlsanity.com/paper/1503.03585/) (2015)
- [Neural Ordinary Differential Equations](https://mlsanity.com/paper/1806.07366/) (2018)
- [Learning to summarize from human feedback](https://mlsanity.com/paper/2009.01325/) (2020)
- [Training Diffusion Models with Reinforcement Learning](https://mlsanity.com/paper/2305.13301/) (2023)
- [Diffusion Model Alignment Using Direct Preference Optimization](https://mlsanity.com/paper/2311.12908/) (2023)
- [Advantage-Weighted Regression: Simple and Scalable Off-Policy Reinforcement Learning](https://mlsanity.com/paper/1910.00177/) (2019)
- [Flow Network based Generative Models for Non-Iterative Diverse Candidate Generation](https://mlsanity.com/paper/2106.04399/) (2021)
- [Path Integral Sampler: a stochastic control approach for sampling](https://mlsanity.com/paper/2111.15141/) (2021)
- [AlphaFold Meets Flow Matching for Generating Protein Ensembles](https://mlsanity.com/paper/2402.04845/) (2024)
- [Improved sampling via learned diffusions](https://mlsanity.com/paper/2307.01198/) (2023)
- [A theory of continuous generative flow networks](https://mlsanity.com/paper/2301.12594/) (2023)
- [Two for One: Diffusion Models and Force Fields for Coarse-Grained Molecular Dynamics](https://mlsanity.com/paper/2302.00600/) (2023)
- [EigenFold: Generative Protein Structure Prediction with Diffusion Models](https://mlsanity.com/paper/2304.02198/) (2023)
- [Reliability and Learnability of Human Bandit Feedback for Sequence-to-Sequence Reinforcement Learning](https://mlsanity.com/paper/1805.10627/) (2018)
- [Generative Modeling of Molecular Dynamics Trajectories](https://mlsanity.com/paper/2409.17808/) (2024)
- [OpenMM 8: Molecular Dynamics Simulation with Machine Learning Potentials](https://mlsanity.com/paper/2310.03121/) (2023)
- [Protein Conformation Generation via Force-Guided SE(3) Diffusion Models](https://mlsanity.com/paper/2403.14088/) (2024)
- [Antigen-Specific Antibody Design via Direct Energy-based Preference Optimization](https://mlsanity.com/paper/2403.16576/) (2024)
- [Str2Str: A Score-based Framework for Zero-shot Protein Conformation Sampling](https://mlsanity.com/paper/2306.03117/) (2023)
- [Aligning Target-Aware Molecule Diffusion Models with Exact Energy Optimization](https://mlsanity.com/paper/2407.01648/) (2024)
- [Structure Language Models for Protein Conformation Generation](https://mlsanity.com/paper/2410.18403/) (2024)

## Built on by (most cited first, 5 of 5)

- [SimpleFold: Folding Proteins is Simpler than You Think](https://mlsanity.com/paper/2509.18480/) (2025)
- [Atomic Trajectory Modeling with State Space Models for Biomolecular Dynamics](https://mlsanity.com/paper/2603.17633/) (2026)
- [Learning Structure, Energy, and Dynamics: A Survey of Artificial Intelligence for Protein Dynamics](https://mlsanity.com/paper/2604.25244/) (2026)
- [All-Atom GPCR-Ligand Dynamics Simulation via a Residual Latent Flow Mode](https://mlsanity.com/paper/2602.03902/) (2026)
- [From Snapshots to Symphonies: The Evolution of Protein Prediction from Static Structures to Generative Dynamics and Multimodal Interactions](https://mlsanity.com/paper/2603.18505/) (2026)

## Abstract (arXiv)

Protein dynamics play a crucial role in protein biological functions and properties, and their traditional study typically relies on time-consuming molecular dynamics (MD) simulations conducted in silico. Recent advances in generative modeling, particularly denoising diffusion models, have enabled efficient accurate protein structure prediction and conformation sampling by learning distributions over crystallographic structures. However, effectively integrating physical supervision into these data-driven approaches remains challenging, as standard energy-based objectives often lead to intractable optimization. In this paper, we introduce Energy-based Alignment (EBA), a method that aligns generative models with feedback from physical models, efficiently calibrating them to appropriately balance conformational states based on their energy differences. Experimental results on the MD ensemble benchmark demonstrate that EBA achieves state-of-the-art performance in generating high-quality protein ensembles. By improving the physical plausibility of generated structures, our approach enhances model predictions and holds promise for applications in structural biology and drug discovery.