The Shakhnovich Biophysics Lab works on a broad range of topics from Molecular Evolution and Origins of Life to Drug Discovery. Our approach integrates theoretical, computational and experimental work. See our Research page for more details.
"Coral Reef" model of active cytoplasm: Protein Quality Control (PQC) shapes fitness effects of mutations. Components that belong to opposite branches of PQC – chaperonins (GroEL) and ATP-dependent proteases (Lon) – act on equilibrium Molten Globule folding intermediate of an essential protein (DHFR) in E. coli cytoplasm. Changes in the chromosomal folA gene encoding DHFR were introduced by making point mutations or by replacing the the gene altogether by its orthologs from a range of bacterial species. Relative fitness of the folA mutant and orthologous-replacement E coli strains is determined by the amount of soluble DHFR in their cytoplasm. The abundance of soluble DHFR is established in dynamic steady-state where production and GroEL-assisted folding is balanced by proteolytic digestion of DHFR in its Molten Globule state by the ATP-dependent protease Lon.