Natural evolution explores vast sequence space for rare mutations, and learning from it can guide artificial evolution. A study found that general protein language models can efficiently evolve human antibodies by suggesting evolutionarily plausible mutations, even without target antigen, binding specificity, or protein structure information. Language-model-guided affinity maturation improved the binding affinities of clinically relevant antibodies up to sevenfold and unmatured antibodies up to 160-fold, with favorable thermostability and viral neutralization activity. The models also guided efficient evolution across diverse protein families and selection pressures.
Natural evolution must explore a vast landscape of possible sequences for desirable yet rare mutations, suggesting that learning from natural evolutionary strategies could guide artificial evolution. Here we report that general protein language models can efficiently evolve human antibodies by suggesting mutations that are evolutionarily plausible, despite providing the model with no information about the target antigen, binding specificity or protein structure. We performed language-model-guided affinity maturation of seven antibodies, screening 20 or fewer variants of each antibody across only two rounds of laboratory evolution, and improved the binding affinities of four clinically relevant, highly mature antibodies up to sevenfold and three unmatured antibodies up to 160-fold, with many designs also demonstrating favorable thermostability and viral neutralization activity against Ebola and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pseudoviruses. The same models that improve antibody binding also guide efficient evolution across diverse protein families and selection pressures, including antibiotic resistance and enzyme activity, suggesting that these results generalize to many settings. A general protein language model guides protein evolution with 20 or fewer variants needed for testing.
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