Figure 5.
Atomistic simulations predict that co-translational folding significantly improves native RBD formation rate and yield. (a) Probability, as a function of translation length, that cysteine pairs (as indicated in legend) make contact within 5 Å of each other as predicted by atomistic simulation. (b) Schematic of kinetic model, detailed in the main text and materials and methods sections. In our kinetic model, opening and closing transitions that unite or separate cysteine pairs (double arrows) are assumed to occur on much faster timescales than oxidation (single arrows pointing right) (per Eq. 3). At a given length, any permutation of new disulfides involving unpaired cysteines may form, provided these cysteines have been translated; one possible sequence of disulfide formation events involving the first two translation lengths is shown here. (c) Solutions to kinetic model showing probability, as a function of time, of forming native species containing various permutations of the four native disulfides (indicated above respective curves) as well as trapped species containing the 28–58 nonnative disulfide (red line), assuming either that folding begins co-translationally per the kinetic model in (b) (top panel) or does not begin until synthesis is complete (bottom panel). The x axis depicts time normalized by the time needed to translate the full RBD; we note that synthesis must be complete before the final disulfide involving C-terminal residue 192 can form. We note that each line corresponds to the probability of a state with “only” the indicated disulfides formed. Formation of additional disulfides corresponds to a transition out of that state, hence why the probabilities that states with incomplete disulfides (e.g., the 3–28 and 46–99 state) always drop after an initial rise. The insets show zoomed-in traces corresponding to the state with all disulfides formed between normalized time values 1 (corresponding to immediately after translation) and 2. In this panel, the unknown intrinsic oxidation/translation rate ratio, is set to 5.