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Publication Abstract from PubMed

The aggregation propensity of each particular protein seems to be shaped by evolution according to its natural abundance in the cell. The production and downstream processing of recombinant polypeptides implies attaining concentrations that are orders of magnitude above their natural levels, often resulting in their aggregation; a phenomenon that precludes the marketing of many globular proteins for biomedical or biotechnological applications. Therefore, there is a huge interest in methods aimed to rise proteins solubility above their natural limits. Here, we demonstrate that an updated version of our AGGRESCAN 3D structural aggregation predictor, that now takes into account protein stability, allows designing mutations at specific positions in the structure that improve the solubility of proteins without compromising their conformation. Using this approach, we have designed a highly soluble variant of the Green Fluorescent Protein (GFP) and a human single-domain VH antibody displaying significantly reduced aggregation propensity. Overall, our data indicate that the solubility of unrelated proteins can be easily tuned by in silico-designed non-destabilizing amino acid changes at their surfaces.

Combining structural aggregation propensity and stability predictions to re-design protein solubility.,Gil-Garcia M, Bano-Polo M, Varejao N, Jamroz M, Kuriata A, Diaz Caballero M, Lascorz J, Morel B, Navarro S, Reverter D, Kmiecik S, Ventura S Mol Pharm. 2018 Jul 23. doi: 10.1021/acs.molpharmaceut.8b00341. PMID:30036481^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.