Thread by @connor_rosen

Super neat story on how cellular quality control impacts the mutational landscape of proteins - beneficial mutations in DHFR during deep mutational scanning are totally altered dependent on cellular QC #Biophysics #Evolution biorxiv.org/content/10.110… Way to go! @KortemmeLab

In an initial DMS experiment on DHFR, there were a large number (25% of all sequences!) of advantageous mutations spread across the whole protein. Reintroduction of QC protein Lon reduced the number of advantageous mutants and lowered average benefit of those mutations

Changes in selection coefficient (the “advantageous-ness”) were most striking at hydrophobic/aromatic residues and buried residues - and these correlate with Tm changes of variants. So Lon seems to be imposing higher standards on DHFR, particularly for destabilizing core mutants

Very good summary figure - in the -Lon selection, you see beneficial mutations (red) through the protein, including in buried (no cross-hatch pattern) areas, avoiding only catalytic hydride transfer site, whereas +Lon selection has a lot more restricted sites (blue)

This is another fantastic demonstration that protein dynamics/stability are coupled with evolvability, and the authors propose a cool selection scheme where modulation of cellular state may be used to push antibiotic resistance mutations into favorable/unfavorable positions