AbDiffuser: Full-Atom Generation of in vitro Functioning Antibodies

TL;DR

AbDiffuser is a novel physics-informed diffusion model that jointly generates antibody structures and sequences, demonstrating high-quality in silico and in vitro results, including successful discovery of functional HER2 antibodies.

Contribution

It introduces a new equivariant diffusion framework with physics-based constraints for full-atom antibody generation, improving efficiency and accuracy over prior methods.

Findings

Generated antibodies closely match reference sequences and structures.

All 16 HER2 antibodies were successfully expressed in vitro.

57.1% of designed antibodies were confirmed as tight binders.

Abstract

We introduce AbDiffuser, an equivariant and physics-informed diffusion model for the joint generation of antibody 3D structures and sequences. AbDiffuser is built on top of a new representation of protein structure, relies on a novel architecture for aligned proteins, and utilizes strong diffusion priors to improve the denoising process. Our approach improves protein diffusion by taking advantage of domain knowledge and physics-based constraints; handles sequence-length changes; and reduces memory complexity by an order of magnitude, enabling backbone and side chain generation. We validate AbDiffuser in silico and in vitro. Numerical experiments showcase the ability of AbDiffuser to generate antibodies that closely track the sequence and structural properties of a reference set. Laboratory experiments confirm that all 16 HER2 antibodies discovered were expressed at high levels and that 57.1% of the selected designs were tight binders.