![]() ![]() A recent in vivo study from our lab also showed that the chaperone action in dynamic cellular milieu can be pleiotropic, i.e. Lindquist and others posited that chaperones may act as phenotypic capacitors by buffering the fitness effects of deleterious mutations, leading to a greater genetic diversity and speeding up adaptive evolution. ![]() Chaperonins, like GroEL, effectively catalyze the folding process by increasing the rate at which misfolded proteins are converted into their folded conformations – this process can lead to diminished aggregation and NF-PPIs due to the limited presence of aggregation-prone misfolded species in the cytoplasm. In three domains of life, chaperones are essential components of protein homeostatic machinery. įrom de novo folding of nascent polypeptides to refolding of mature misfolded proteins, chaperones or heat-shock proteins assist in maintaining the necessary abundance of folded proteins, compensating for the selective costs of erroneous protein synthesis, misfolding, and sequestration of proteins in NF-PPIs. However, other constraints such as the need to avoid protein sequestration to non-functional protein-protein interactions (NF-PPIs) in the cytoplasm are also emerging as important determinants of the rates and outcomes of evolutionary dynamics of proteins –. It is widely accepted that strong selective pressure against protein misfolding plays a key role in determining the rate of protein evolution and sustainable mutational loads –. Imposing simultaneous and often contradictive (pleiotropic) constraints on protein sequence evolution severely limits the repertoire of possible solutions in sequence space and thus slows down the evolutionary dynamics. folding stability and kinetics), molecular function, as well as interactions with other proteins in the cellular milieu should be simultaneously optimized. As a result, chaperones dramatically accelerate adaptation dynamics.Įvolutionary selection of protein sequences is a complex task whereby several traits such as translation efficiency, structural integrity (i.e. We find that by catalyzing protein folding chaperones buffer the deleterious effect of mutations on folding stability and thus open up a sequence space for efficient and simultaneous optimization of multiple molecular traits determining the cellular fitness. We use a 6-loci multi scale model of cell populations, where the fitness of each cell is determined from its genome, based on statistical mechanical principles of protein folding and protein-protein interactions. Here we explore computationally the consequences of chaperone activity in cytoplasm via long-time evolutionary dynamics simulations. 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. ![]()
0 Comments
Leave a Reply. |
AuthorWrite something about yourself. No need to be fancy, just an overview. ArchivesCategories |