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Abstract Protein sequence design, also known as protein inverse folding, is a crucial task in protein engineering and design. Despite the recent advancements in this field, which have facilitated the identification of amino acid sequences based on backbone structures, achieving higher levels of accuracy in sequence recovery rates remains challenging. It this study, we introduce a two-stage protein sequence design method named OPUS-Design. Our evaluation on recently released targets from CAMEO and CASP15 shows that OPUS-Design significantly surpasses several other leading methods on both monomer and oligomer targets in terms of sequence recovery rate. Furthermore, by utilizing its finetune version OPUS-Design-ft and our previous work OPUS-Mut, we have successfully designed a thermal-tolerant double-point mutant of T4 lysozyme that demonstrates a residual enzyme activity exceeding that of the wild-type T4 by more than twofold when both are subjected to extreme heat treatment at 70°C. Importantly, this accomplishment is achieved through the experimental verification of less than 10 mutant candidates, thus significantly alleviating the burden of experimental verification process.
Xu et al. (Wed,) studied this question.