# A Simple yet Effective DDG Predictor is An Unsupervised Antibody Optimizer and Explainer

arXiv: https://arxiv.org/abs/2502.06913 · HTML: https://mlsanity.com/paper/2502.06913/

## Key facts

- No citing papers in the map yet (data through 14 Oct 2026).
- Builds on 11 of its 42 references that are in the map.
- First posted on arXiv 10 Feb 2025.

## Builds on (most cited first, 11 of 11)

- [Distilling the Knowledge in a Neural Network](https://mlsanity.com/paper/1503.02531/) (2015)
- [Iterative Refinement Graph Neural Network for Antibody Sequence-Structure Co-design](https://mlsanity.com/paper/2110.04624/) (2021)
- [Tranception: protein fitness prediction with autoregressive transformers and inference-time retrieval](https://mlsanity.com/paper/2205.13760/) (2022)
- [Conditional Antibody Design as 3D Equivariant Graph Translation](https://mlsanity.com/paper/2208.06073/) (2022)
- [End-to-End Full-Atom Antibody Design](https://mlsanity.com/paper/2302.00203/) (2023)
- [MAPE-PPI: Towards Effective and Efficient Protein-Protein Interaction Prediction via Microenvironment-Aware Protein Embedding](https://mlsanity.com/paper/2402.14391/) (2024)
- [Improving Molecular Design by Stochastic Iterative Target Augmentation](https://mlsanity.com/paper/2002.04720/) (2020)
- [Learning to Predict Mutation Effects of Protein-Protein Interactions by Microenvironment-aware Hierarchical Prompt Learning](https://mlsanity.com/paper/2405.10348/) (2024)
- [Predicting mutational effects on protein-protein binding via a side-chain diffusion probabilistic model](https://mlsanity.com/paper/2310.19849/) (2023)
- [Relation-Aware Equivariant Graph Networks for Epitope-Unknown Antibody Design and Specificity Optimization](https://mlsanity.com/paper/2501.00013/) (2024)
- [Multi-level Interaction Modeling for Protein Mutational Effect Prediction](https://mlsanity.com/paper/2405.17802/) (2024)

## Abstract (arXiv)

The proteins that exist today have been optimized over billions of years of natural evolution, during which nature creates random mutations and selects them. The discovery of functionally promising mutations is challenged by the limited evolutionary accessible regions, i.e., only a small region on the fitness landscape is beneficial. There have been numerous priors used to constrain protein evolution to regions of landscapes with high-fitness variants, among which the change in binding free energy (DDG) of protein complexes upon mutations is one of the most commonly used priors. However, the huge mutation space poses two challenges: (1) how to improve the efficiency of DDG prediction for fast mutation screening; and (2) how to explain mutation preferences and efficiently explore accessible evolutionary regions. To address these challenges, we propose a lightweight DDG predictor (Light-DDG), which adopts a structure-aware Transformer as the backbone and enhances it by knowledge distilled from existing powerful but computationally heavy DDG predictors. Additionally, we augmented, annotated, and released a large-scale dataset containing millions of mutation data for pre-training Light-DDG. We find that such a simple yet effective Light-DDG can serve as a good unsupervised antibody optimizer and explainer. For the target antibody, we propose a novel Mutation Explainer to learn mutation preferences, which accounts for the marginal benefit of each mutation per residue. To further explore accessible evolutionary regions, we conduct preference-guided antibody optimization and evaluate antibody candidates quickly using Light-DDG to identify desirable mutations.