Increasing Protein Production Rates Can Decrease the Rate at Which Functional Protein is Produced and Their Steady-State Levels

The rate at which soluble, functional protein is produced by the ribosome has recently been found to vary in complex and unexplained ways as various translation-associated rates are altered through synonymous codon substitutions. To understand this phenomenon, here, we combine a well-established ribosome-traffic model with a master-equation model of cotranslational domain folding to explore the scenarios that are possible for the protein production rate, J, and the functional-nascent protein production rate, F, as the rates of various translation processes are altered for five different E. coli proteins. We find that while J monotonically increases as the rates of translation-initiation, -elongation, and -termination increase, F can either increase or decrease. We show that F's nonmonotonic behavior arises within the model from two opposing trends: the tendency for increased translation rates to produce more total protein but less cotranslationally folded protein. We further demonstrate that under certain conditions these nonmonotonic changes in F can result in nonmonotonic variations in post-translational, steady-state levels of functional protein. These results provide a potential explanation for recent experimental observations in which the specific activity of enzymatic proteins decreased with increased synthesis rates. Additionally our model has the potential to be used to rationally design transcripts to maximize the production of functional nascent protein by simultaneously optimizing translation initiation, elongation, and termination rates.