Benchmarking antigen-aware inverse folding methods for antibody design

Abstract Computational antibody design has seen many recent advances pioneered via the use of language models and advanced structure prediction tools. Developing a de novo antibody against a specific antigen requires structural awareness that most language models lack. A prominent class of machine learning methods combining the best of language model and structural worlds is inverse folding. This approach aims to predict a sequence that would fit a given structure. Such methods are now increasingly used to predict alternate sequences given a structure of a binder. It is known that, just like language models, such methods have certain predictive power in identifying binders. Here we performed a set of tests to reveal where, if at all, such methods provide value in the realistic setting of antibody discovery.