Fig. 4.

Hsp90 mediates a trade-off between stability and aggregation propensity. a Effect of buried hydrophobicity on protein stability and aggregation propensity. b Sites with increased hydrophobic variants (Site_hydro) in Hsp90_N and hsp90_i populations. c Properties of P1 destabilized sites (Site_destab) from Hsp90_N and hsp90_i: aggregation propensity (left panel) and hydrophobicity (right panel). d Distinct nature of destabilizing variants (Site_destab) in P1 of Hsp90_N and hsp90_i populations. Original amino acid is indicated in the middle. Color indicates side-chain properties: Yellow, hydrophobic; gray, polar; green, charged. Mutations to specific residues in Hsp90_N (left) and hsp90_i (right) are indicated, where circle size indicates mutation occurrence. The width of lines connecting each mutation represents the number of occurrences for each variant. e Exemplar P1 variants enriched in Hsp90_N and hsp90_i populations. Location in P1 folded structure and effects on stability, aggregation propensity, and hydrophobicity are indicated. Mutations A195V and P263L (blue) observed in Hsp90_N, and L269Q (red) in hsp90_i. Structure from 2PLV, with VP2 monomer, and assembled capsid indicated. f Schematic effect of Hsp90 on sequence space. Hsp90 allows variants to explore a region in sequence space of increased hydrophobicity and aggregation propensity, but also of increased stability. Lower Hsp90 constrains sequence space variants to a region of reduced stability, hydrophobicity, and aggregation propensity. For boxplots, the center line represents the median, the bound box the interquartile range, and the whiskers 1.5× the interquartile range. Significance: *p < 0.05; **p < 0.01; ***p < 0.005 by two-tail Fisher’s exact test or Mann–Whitney–Wilcoxon test