Physical Origins of Codon Positions That Strongly Influence Cotranslational Folding: A Framework for Controlling Nascent-Protein Folding

An
emerging paradigm in the field of in vivo protein biophysics
is that nascent-protein behavior is a type of nonequilibrium phenomenon,
where translation-elongation kinetics can be more important in determining
nascent-protein behavior than the thermodynamic properties of the
protein. Synonymous codon substitutions, which change the translation
rate at select codon positions along a transcript, have been shown
to alter cotranslational protein folding, suggesting that evolution
may have shaped synonymous codon usage in the genomes of organisms
in part to increase the amount of folded and functional nascent protein.
Here, we develop a Monte Carlo-master-equation method that allows
for the control of nascent-chain folding during translation through
the rational design of mRNA sequences to guide the cotranslational
folding process. We test this framework using coarse-grained molecular
dynamics simulations and find it provides optimal mRNA sequences to
control the simulated, cotranslational folding of a protein in a user-prescribed
manner. With this approach we discover that some codon positions in
a transcript can have a much greater impact on nascent-protein folding
than others because they tend to be positions where the nascent chain
populates states that are far from equilibrium, as well as being dependent
on a complex ratio of time scales. As a consequence, different cotranslational
profiles of the same protein can have different critical codon positions
and different numbers of synonymous mRNA sequences that encode for
them. These findings explain that there is a fundamental connection
between the nonequilibrium nature of cotranslational processes, nascent-protein
behavior, and synonymous codon usage.