The rate of the molecular clock and the cost of gratuitous protein synthesis

We show that the cost of toxic protein misfolding is small compared to other costs associated with protein synthesis. Complementary computational analyses demonstrate that there is also a relatively weaker, but statistically significant, selection for increasing solubility and polarity in highly expressed E. coli proteins.Although we cannot rule out the possibility that selection against misfolding toxicity significantly affects the protein clock in species other than E. coli, our results suggest that it is unlikely to be the dominant and universal factor determining the clock rate in all organisms. We find that in this bacterium other costs associated with protein synthesis are likely to play an important role. Interestingly, our experiments also suggest significant costs associated with volume effects, such as jamming of the cellular environment with unnecessary proteins.Once the first protein sequences became available, their comparison led to the conclusion that the number of accumulated substitutions between orthologs was mainly a function of the evolutionary time elapsed since the last common ancestor of corresponding species [1,2]. Consequently, orthologous proteins accumulate substitutions at an approximately constant rate over long evolutionary intervals. This observation suggests that one can use available protein sequences as a molecular clock to estimate divergence times between different species [3]. Further studies revealed that while the pace of the molecular clock is similar for orthologous proteins in different lineages, it varies by several orders of magnitude across non-orthologous proteins [4,5].For several decades the dominant hypothesis explaining the large variability of the molecular clock rate between non-orthologous proteins was based on the concept of functional protein density: the higher the fraction of protein residues directly involved in its function, the slower the protein molecular clock [6,7]. It was not until high-throughput genom