Hsp90 influences protein evolution by balancing evolutionary trade-offs between protein stability and aggregation

Acquisition of mutations is central to evolution; however, the detrimental effects of most mutations on protein folding and stability limit protein evolvability. Molecular chaperones, which suppress aggregation and facilitate polypeptide folding, may alleviate the effects of destabilizing mutations thus promoting sequence diversification. To illuminate how chaperones control protein evolution , we here examine the effect of reducing the activity of chaperone Hsp90 on poliovirus evolution. We find that Hsp90 offsets the evolutionary trade-off between protein stability and aggregation. Lower chaperone levels favour variants of reduced hydrophobicity, decreasing protein aggregation propensity but at a cost to protein stability. Notably, reducing Hsp90 activity also promotes clusters of codon-deoptimized synonymous mutations at inter-domain boundaries, likely to facilitate cotranslational domain folding. Our results reveal how a chaperone can shape the sequence landscape at both the protein and RNA levels to harmonize competing constraints posed by protein stability, aggregation propensity and translation rate on successful protein biogenesis.