Antibody complementarity-determining region design using AlphaFold2 and DDG predictor

Abstract

The constraints imposed by natural antibody affinity maturation often culminate in antibodies with suboptimal binding affinities, thereby limiting their therapeutic efficacy. As such, the augmentation of antibody binding affinity is pivotal for the advancement of efficacious antibody-based therapies. Classical experimental paradigms for antibody engineering are financially and temporally prohibitive due to the extensive combinatorial space of sequence variations in the complementarity-determining regions (CDRs). The advent of computational techniques presents a more expeditious and economical avenue for the systematic design and optimization of antibodies. In this investigation, we assess the performance of AlphaFold2 coupled with the binder hallucination technique for the computational refinement of antibody sequences to elevate the binding affinity of pre-existing antigen-antibody complexes. These methodologies exhibit the capability to predict protein tertiary structures with remarkable fidelity, even in the absence of empirically derived data. Our results intimate that the proposed approach is adept at designing antibodies with improved affinities for antigen-antibody complexes unrepresented in AlphaFold2’s training dataset, underscoring its potential as a robust and scalable strategy for antibody engineering.