Protein aggregation limits recombinant protein production, motivating the development of shortsolubility-enhancing and protective peptides. We combined computational library design withexperimental selection to explore variants derived from intrinsically disordered NEXT and SSBtags and the CAHS1 protective protein. NEXT and SSB libraries were evaluated usingcarbenicillin selection linked to aggregation-prone β-lactamase while CAHS1 variantsunderwent freeze-thaw selection. Sequencing of variants revealed changes in variantcomposition across all three libraries, supported by Monte Carlo-calibrated chi-squared tests.Property based clustering associated NEXT and SSB enrichment with greater predicted chargeand hydrophilicity. There is also an enrichment of CAHS1 variants with a stronger amphiphilichelical character. These findings identify candidate property trends and sequences for furtherinvestigation. Further work is required to characterise reproducibility of findings and quantifyprotein solubility. This workflow provides a foundation for subsequent evolution and validationof IDP-derived solubility enhancers and protective peptides. This dataset provides all raw sequencing data, code outputs, as well as plate and gel images generated from this project. All authors contributed equally.
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