# Joint Design of Protein Surface and Structure Using a Diffusion Bridge Model

arXiv: https://arxiv.org/abs/2511.16675 · HTML: https://mlsanity.com/paper/2511.16675/

## Key facts

- No citing papers in the map yet (data through 14 Oct 2026).
- Builds on 26 of its 63 references that are in the map.
- First posted on arXiv 8 Nov 2025.

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

- [Denoising Diffusion Probabilistic Models](https://mlsanity.com/paper/2006.11239/) (2020)
- [Score-Based Generative Modeling through Stochastic Differential Equations](https://mlsanity.com/paper/2011.13456/) (2020)
- [Deep Unsupervised Learning using Nonequilibrium Thermodynamics](https://mlsanity.com/paper/1503.03585/) (2015)
- [Classifier-Free Diffusion Guidance](https://mlsanity.com/paper/2207.12598/) (2022)
- [Generative Modeling by Estimating Gradients of the Data Distribution](https://mlsanity.com/paper/1907.05600/) (2019)
- [E(n) Equivariant Graph Neural Networks](https://mlsanity.com/paper/2102.09844/) (2021)
- [Maximum Likelihood Training of Score-Based Diffusion Models](https://mlsanity.com/paper/2101.09258/) (2021)
- [Diffusion Schr"odinger Bridge with Applications to Score-Based Generative Modeling](https://mlsanity.com/paper/2106.01357/) (2021)
- [GeoDiff: a Geometric Diffusion Model for Molecular Conformation Generation](https://mlsanity.com/paper/2203.02923/) (2022)
- [Permutation Invariant Graph Generation via Score-Based Generative Modeling](https://mlsanity.com/paper/2003.00638/) (2020)
- [Riemannian Score-Based Generative Modelling](https://mlsanity.com/paper/2202.02763/) (2022)
- [SE(3) diffusion model with application to protein backbone generation](https://mlsanity.com/paper/2302.02277/) (2023)
- [Denoising Diffusion Bridge Models](https://mlsanity.com/paper/2309.16948/) (2023)
- [SE(3)-Stochastic Flow Matching for Protein Backbone Generation](https://mlsanity.com/paper/2310.02391/) (2023)
- [Concrete Score Matching: Generalized Score Matching for Discrete Data](https://mlsanity.com/paper/2211.00802/) (2022)
- [Riemannian Diffusion Models](https://mlsanity.com/paper/2208.07949/) (2022)
- [Protein structure generation via folding diffusion](https://mlsanity.com/paper/2209.15611/) (2022)
- [Diffusion Bridge Implicit Models](https://mlsanity.com/paper/2405.15885/) (2024)
- [Full-Atom Peptide Design based on Multi-modal Flow Matching](https://mlsanity.com/paper/2406.00735/) (2024)
- [PPFlow: Target-aware Peptide Design with Torsional Flow Matching](https://mlsanity.com/paper/2405.06642/) (2024)
- [DiffPack: A Torsional Diffusion Model for Autoregressive Protein Side-Chain Packing](https://mlsanity.com/paper/2306.01794/) (2023)
- [DeepSurf: A surface-based deep learning approach for the prediction of ligand binding sites on proteins](https://mlsanity.com/paper/2002.05643/) (2020)
- [Pre-training of Equivariant Graph Matching Networks with Conformation Flexibility for Drug Binding](https://mlsanity.com/paper/2204.08663/) (2022)
- [SurfPro: Functional Protein Design Based on Continuous Surface](https://mlsanity.com/paper/2405.06693/) (2024)
- [ShEPhERD: Diffusing shape, electrostatics, and pharmacophores for bioisosteric drug design](https://mlsanity.com/paper/2411.04130/) (2024)
- [Hotspot-Driven Peptide Design via Multi-Fragment Autoregressive Extension](https://mlsanity.com/paper/2411.18463/) (2024)

## Abstract (arXiv)

Protein-protein interactions (PPIs) are governed by surface complementarity and hydrophobic interactions at protein interfaces. However, designing diverse and physically realistic protein structure and surfaces that precisely complement target receptors remains a significant challenge in computational protein design. In this work, we introduce PepBridge, a novel framework for the joint design of protein surface and structure that seamlessly integrates receptor surface geometry and biochemical properties. Starting with a receptor surface represented as a 3D point cloud, PepBridge generates complete protein structures through a multi-step process. First, it employs denoising diffusion bridge models (DDBMs) to map receptor surfaces to ligand surfaces. Next, a multi-model diffusion model predicts the corresponding structure, while Shape-Frame Matching Networks ensure alignment between surface geometry and backbone architecture. This integrated approach facilitates surface complementarity, conformational stability, and chemical feasibility. Extensive validation across diverse protein design scenarios demonstrates PepBridge's efficacy in generating structurally viable proteins, representing a significant advancement in the joint design of top-down protein structure.