Evaluation of AlphaFold antibody–antigen modeling with implications for improving predictive accuracy

Abstract

AbstractHigh resolution antibody–antigen structures provide critical insights into immune recognition and can inform therapeutic design. The challenges of experimental structural determination and the diversity of the immune repertoire underscore the necessity of accurate computational tools for modeling antibody–antigen complexes. Initial benchmarking showed that despite overall success in modeling protein–protein complexes, AlphaFold and AlphaFold‐Multimer have limited success in modeling antibody–antigen interactions. In this study, we performed a thorough analysis of AlphaFold's antibody–antigen modeling performance on 427 nonredundant antibody–antigen complex structures, identifying useful confidence metrics for predicting model quality, and features of complexes associated with improved modeling success. Notably, we found that the latest version of AlphaFold improves near‐native modeling success to over 30%, versus approximately 20% for a previous version, while increased AlphaFold sampling gives approximately 50% success. With this improved success, AlphaFold can generate accurate antibody–antigen models in many cases, while additional training or other optimization may further improve performance.