Ig-VAE: Generative modeling of protein structure by direct 3D coordinate generation

While deep learning models have seen increasing applications in protein science, few have been implemented for protein backbone generation—an important task in structure-based problems such as active site and interface design. We present a new approach to building class-specific backbones, using a variational auto-encoder to directly generate the 3D coordinates of immunoglobulins. Our model is torsion- and distance-aware, learns a high-resolution embedding of the dataset, and generates novel, high-quality structures compatible with existing design tools. We show that the Ig-VAE can be used with Rosetta to create a computational model of a SARS-CoV2-RBD binder via latent space sampling. We further demonstrate that the model’s generative prior is a powerful tool for guiding computational protein design, motivating a new paradigm under which backbone design is solved as constrained optimization problem in the latent space of a generative model.Author summary: Many essential biochemical processes are governed by protein-protein interactions (PPIs), and our ability to make binding proteins that modulate PPIs is crucial to the creation of therapeutics and the study of cell-signaling. One critical aspect of PPI design is to capture protein conformational flexibility. Deep generative models are a class of mathematical models that are able to synthesize novel data from a finite set of training examples. Here, we make advances in computational protein design methodology by developing a deep generative model that creates protein backbones adopting the immunoglobulin fold, which is found in natural binding proteins such as antibodies. While generative models have been powerful in tasks such as image generation, using them to create proteins has remained a challenge. We solve this problem with a new model that allows for the direct generation of novel 3D molecules and show that they are of high chemical accuracy. Generated structures work well with existing protein design methods such as Rosetta, providing access to a large collection of novel immunoglobulin structures. Finally, we present a new protein design framework, called “generative design,” that shows how deep generative models such as ours can be applied to virtually any protein design problem.