Sequence-Only Prediction of Binding Affinity Changes: A Robust and Interpretable Model for Antibody Engineering

TL;DR

ProtAttBA is a sequence-only deep learning model that accurately predicts antibody-antigen binding affinity changes, offering a robust, interpretable, and cost-effective tool for antibody engineering without relying on complex structural data.

Contribution

This work introduces ProtAttBA, a novel sequence-based deep learning approach with a pre-training phase and attention mechanism for predicting binding affinity changes.

Findings

Achieves competitive performance on benchmark datasets.

Demonstrates robustness with uncertain structural data.

Provides interpretability through attention scores identifying key residues.

Abstract

A pivotal area of research in antibody engineering is to find effective modifications that enhance antibody-antigen binding affinity. Traditional wet-lab experiments assess mutants in a costly and time-consuming manner. Emerging deep learning solutions offer an alternative by modeling antibody structures to predict binding affinity changes. However, they heavily depend on high-quality complex structures, which are frequently unavailable in practice. Therefore, we propose ProtAttBA, a deep learning model that predicts binding affinity changes based solely on the sequence information of antibody-antigen complexes. ProtAttBA employs a pre-training phase to learn protein sequence patterns, following a supervised training phase using labeled antibody-antigen complex data to train a cross-attention-based regressor for predicting binding affinity changes. We evaluated ProtAttBA on three open benchmarks under different conditions. Compared to both sequence- and structure-based prediction methods, our approach achieves competitive performance, demonstrating notable robustness, especially with uncertain complex structures. Notably, our method possesses interpretability from the attention mechanism. We show that the learned attention scores can identify critical residues with impacts on binding affinity. This work introduces a rapid and cost-effective computational tool for antibody engineering, with the potential to accelerate the development of novel therapeutic antibodies.