# EnerBridge-DPO: Energy-Guided Protein Inverse Folding with Markov Bridges and Direct Preference Optimization

arXiv: https://arxiv.org/abs/2506.09496 · HTML: https://mlsanity.com/paper/2506.09496/

## Key facts

- Cited by 1 papers in the map (data through 14 Oct 2026).
- Builds on 27 of its 55 references that are in the map.
- First posted on arXiv 11 Jun 2025.

## Builds on (most cited first, 27 of 27)

- [Attention Is All You Need](https://mlsanity.com/paper/1706.03762/) (2017)
- [Adam: A Method for Stochastic Optimization](https://mlsanity.com/paper/1412.6980/) (2014)
- [Training language models to follow instructions with human feedback](https://mlsanity.com/paper/2203.02155/) (2022)
- [Direct Preference Optimization: Your Language Model is Secretly a Reward Model](https://mlsanity.com/paper/2305.18290/) (2023)
- [Scalable Diffusion Models with Transformers](https://mlsanity.com/paper/2212.09748/) (2022)
- [Deep reinforcement learning from human preferences](https://mlsanity.com/paper/1706.03741/) (2017)
- [Improved Denoising Diffusion Probabilistic Models](https://mlsanity.com/paper/2102.09672/) (2021)
- [Fine-Tuning Language Models from Human Preferences](https://mlsanity.com/paper/1909.08593/) (2019)
- [Structured Denoising Diffusion Models in Discrete State-Spaces](https://mlsanity.com/paper/2107.03006/) (2021)
- [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)
- [Safe RLHF: Safe Reinforcement Learning from Human Feedback](https://mlsanity.com/paper/2310.12773/) (2023)
- [DPOK: Reinforcement Learning for Fine-tuning Text-to-Image Diffusion Models](https://mlsanity.com/paper/2305.16381/) (2023)
- [Learning from Protein Structure with Geometric Vector Perceptrons](https://mlsanity.com/paper/2009.01411/) (2020)
- [Representing Long-Range Context for Graph Neural Networks with Global Attention](https://mlsanity.com/paper/2201.08821/) (2022)
- [PiFold: Toward effective and efficient protein inverse folding](https://mlsanity.com/paper/2209.12643/) (2022)
- [Structure-informed Language Models Are Protein Designers](https://mlsanity.com/paper/2302.01649/) (2023)
- [Graph Denoising Diffusion for Inverse Protein Folding](https://mlsanity.com/paper/2306.16819/) (2023)
- [AlphaDesign: A graph protein design method and benchmark on AlphaFoldDB](https://mlsanity.com/paper/2202.01079/) (2022)
- [RetroBridge: Modeling Retrosynthesis with Markov Bridges](https://mlsanity.com/paper/2308.16212/) (2023)
- [Generative De Novo Protein Design with Global Context](https://mlsanity.com/paper/2204.10673/) (2022)
- [Knowledge-Design: Pushing the Limit of Protein Design via Knowledge Refinement](https://mlsanity.com/paper/2305.15151/) (2023)
- [Learning to Predict Mutation Effects of Protein-Protein Interactions by Microenvironment-aware Hierarchical Prompt Learning](https://mlsanity.com/paper/2405.10348/) (2024)
- [Diffusion Model with Representation Alignment for Protein Inverse Folding](https://mlsanity.com/paper/2412.09380/) (2024)
- [Bridge-IF: Learning Inverse Protein Folding with Markov Bridges](https://mlsanity.com/paper/2411.02120/) (2024)
- [Multi-level Interaction Modeling for Protein Mutational Effect Prediction](https://mlsanity.com/paper/2405.17802/) (2024)
- [Boltzmann-Aligned Inverse Folding Model as a Predictor of Mutational Effects on Protein-Protein Interactions](https://mlsanity.com/paper/2410.09543/) (2024)

## Built on by (most cited first, 1 of 1)

- [g-DPO: Scalable Preference Optimization for Protein Language Models](https://mlsanity.com/paper/2510.19474/) (2025)

## Abstract (arXiv)

Designing protein sequences with optimal energetic stability is a key challenge in protein inverse folding, as current deep learning methods are primarily trained by maximizing sequence recovery rates, often neglecting the energy of the generated sequences. This work aims to overcome this limitation by developing a model that directly generates low-energy, stable protein sequences. We propose EnerBridge-DPO, a novel inverse folding framework focused on generating low-energy, high-stability protein sequences. Our core innovation lies in: First, integrating Markov Bridges with Direct Preference Optimization (DPO), where energy-based preferences are used to fine-tune the Markov Bridge model. The Markov Bridge initiates optimization from an information-rich prior sequence, providing DPO with a pool of structurally plausible sequence candidates. Second, an explicit energy constraint loss is introduced, which enhances the energy-driven nature of DPO based on prior sequences, enabling the model to effectively learn energy representations from a wealth of prior knowledge and directly predict sequence energy values, thereby capturing quantitative features of the energy landscape. Our evaluations demonstrate that EnerBridge-DPO can design protein complex sequences with lower energy while maintaining sequence recovery rates comparable to state-of-the-art models, and accurately predicts Delta Delta G values between various sequences.