![]() ![]() Importantly, chaperones have often been implicated as phenotypic capacitors since they buffer the deleterious effects of mutations, promote genetic diversity, and thus speed up adaptive evolution. Molecular chaperones or heat-shock proteins are essential components of protein homeostatic machinery in all three domains of life, whose role is not only to prevent protein aggregation but also catalyze the protein folding process by decreasing the energetic barrier for folding. A key experimentally testable prediction emerging from our analysis is that down-regulation of chaperones that catalyze protein folding significantly slows down the adaptation dynamics. ![]() We find that by partially releasing the constraint on protein stability, active chaperones promote a deeper exploration of sequence space to strengthen functional PPIs, and diminish the non-functional PPIs. We find that an active chaperone mechanism, whereby chaperones directly catalyze protein folding, has a significant impact on the cellular fitness and the rate of evolutionary dynamics, while passive chaperones, which just maintain misfolded proteins in soluble complexes have a negligible effect on the fitness. Model proteins can exist in native and molten globule states and participate in functional and all possible promiscuous non-functional PPIs. A genotype-phenotype relationship that is based on a simple yet non-trivially postulated protein-protein interaction (PPI) network determines the cell division rate. The 6-loci genomes of model cells encode model proteins, whose folding and interactions in cellular milieu can be evaluated exactly from their genome sequences. Here we developed a physics-based ab initio multi-scale model of a living cell for population dynamics simulations to elucidate the effect of chaperones on adaptive evolution. Although molecular chaperones are essential components of protein homeostatic machinery, their mechanism of action and impact on adaptation and evolutionary dynamics remain controversial. ![]()
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