GENERALIST: A latent space based generative model for protein sequence families

Generative models of protein sequence families are an important tool in the repertoire of protein scientists and engineers alike. However, state-of-the-art generative approaches face inference, accuracy, and overfitting- related obstacles when modeling moderately sized to large proteins and/or protein families with low sequence coverage. Here, we present a simple to learn, tunable, and accurate generative model, GENERALIST: GENERAtive nonLInear tenSor-factorizaTion for protein sequences. GENERALIST accurately captures several high order summary statistics of amino acid covariation. GENERALIST also predicts conservative local optimal sequences which are likely to fold in stable 3D structure. Importantly, unlike current methods, the density of sequences in GENERALIST-modeled sequence ensembles closely resembles the corresponding natural ensembles. Finally, GENERALIST embeds protein sequences in an informative latent space. GENERALIST will be an important tool to study protein sequence variability.Author summary: Protein sequence families show tremendous sequence variation. Yet, it is thought that a large portion of the functional sequence space remains unexplored. Generative models are machine learning methods that allow us to learn what makes proteins functional using sequences of naturally occurring proteins. Here, we present a new type of generative model GENERALIST: GENERAtive nonLInear tenSor-factorizaTion for protein sequences that is accurate, easy to implement, and works with very small datasets. We believe that GENERALIST will be an important tool in the repertoire of protein scientists and engineers alike.