Accurate and robust protein sequence design with CarbonDesign

Protein sequence design is critically important for protein engineering. Despite recent advancements in deep learning-based methods, achieving accurate and robust sequence design remains a challenge. Here we present CarbonDesign, an approach that draws inspiration from successful ingredients of AlphaFold and which has been developed specifically for protein sequence design. At its core, CarbonDesign introduces Inverseformer, which learns representations from backbone structures and an amortized Markov random fields model for sequence decoding. Moreover, we incorporate other essential AlphaFold concepts into CarbonDesign: an end-to-end network recycling technique to leverage evolutionary constraints from protein language models and a multitask learning technique for generating side-chain structures alongside designed sequences. CarbonDesign outperforms other methods on independent test sets including the 15th Critical Assessment of protein Structure Prediction (CASP15) dataset, the Continuous Automated Model Evaluation (CAMEO) dataset and de novo proteins from RFDiffusion. Furthermore, it supports zero-shot prediction of the functional effects of sequence variants, making it a promising tool for applications in bioengineering. Deep learning has led to great advances in predicting protein structure from sequences. Ren and colleagues present here a method for the inverse problem of finding a sequence that results in a desired protein structure, which is inspired by various components of AlphaFold combined with Markov random fields to decode sequences more efficiently.