AntiFold: improved structure-based antibody design using inverse folding

Abstract

Summary: The design and optimization of antibodies requires an intricate balance across multiple properties. Protein inverse folding models, capable of generating diverse sequences folding into the same structure, are promising tools for maintaining structural integrity during antibody design. Here, we present AntiFold, an antibody-specific inverse folding model, fine-tuned from ESM-IF1 on solved and predicted antibody structures. AntiFold outperforms existing inverse folding tools on sequence recovery across complementarity-determining regions, with designed sequences showing high structural similarity to their solved counterpart. It additionally achieves stronger correlations when predicting antibody-antigen binding affinity in a zero-shot manner. AntiFold assigns low probabilities to mutations that disrupt antigen binding, synergizing with protein language model residue probabilities, and demonstrates promise for guiding antibody optimization while retaining structure-related properties.

Availability and implementation: AntiFold is freely available under the BSD 3-Clause as a web server (https://opig.stats.ox.ac.uk/webapps/antifold/) and pip-installable package (https://github.com/oxpig/AntiFold).

Figure 1.

Structure-constrained antibody design with AntiFold. The user inputs an antibody variable domain PDB structure (heavy and light chain) and specifies an IMGT region to design. AntiFold outputs for each residue position in the PDB: (i) residue probabilities, (ii) a number of designed sequences (default 10) for the selected region, predicted to maintain its structural fold, and (iii) structural tolerance to mutations without altering the backbone structure. The diversity of the generated sequences may be controlled with a temperature parameter. AntiFold achieved (iv) state-of-the-art CDRH3 sequence recovery and (v) inverse folding zero-shot binding affinity prediction on an anti-lysozyme antibody dataset (Warszawski et al. 2019).