| Description |
Hidden alterations in genetic code are a rich source of genetic variations that harbors the potential for the evolution of new traits. Genetic variations in protein coding regions may be concealed by protein folding machinery, and molecular chaperones have been implicated in this process. Here we investigate if chemical milieu of cells has the potential to alleviate intracellular protein folding; this would implicate the role of small-molecules in concealing genetic variations. Using model osmolyte TMAO we uncover that it has the potential to buffer mutations that impose kinetic traps in folding pathways. Using this information we rationally designed TMAO-dependent mutants in vivo, starting from a TMAO-independent protein. Strikingly, we delineate different osmolytes to have non-identical specificity for mutational buffering. Consequently, chemical milieu of cells may alter folding pathways of unique mutant variants in polymorphic populations and lead to unanticipated spectrum of genetic buffering.
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