amino acids - Why does protein folding not depend on the order in which it is synthesized?

I read an article recently, written by researcher from Department of Biochemistry, University of Washington, which stated that:

Similarly, success in de novo protein design bears on the question I get after every talk about the importance of the order of chain synthesis on the ribosome to protein folding; computational protein design calculations completely ignore the order of synthesis which hence cannot be critical to protein folding.

I was wondering, how could it be that the form that the protein is folded to, does not have anything to do with the amino-acid sequence that constitute this protein? What I mean, is in case I look at mirror image of a protein, would it fold the same? if I consider for example the sequencers: ser-gly-ala-glu-pro-asp and asp-pro-glu-ala-gly-ser, will they both fold the same? (I think those are d-protein and it's l-protein counterpart)

Can anyone provide evidence that this is, in fact, so. Or do I misunderstand the section quoted?

link to the paper: sci-hub.tw/10.1002/pro.3588

Answer

how could it be that the form that the protein is folded to, does not have anything to do with the amino-acid sequence that constitute this protein?

The quote by the researcher says that the form is unrelated to the direction of synthesis (N->C rather than C->N). It implies that all that matters is the amino-acid sequence that constitutes the protein, and that protein folding is driven by thermodynamic stability rather than by kinetics.

in case I look at mirror image of a protein, would it fold the same?

Yes, if you had an exact mirror image of a protein alone in solution it would adopt the same fold but mirrored. The N and C-temini would be on the same amino acids but all amino acids would be D rather than L chirality. This molecule would not generally be found in biology, since typically life uses L-amino acids. It would have different enzymatic behaviour on chiral molecules.

if I consider for example the sequences: ser-gly-ala-glu-pro-asp and asp-pro-glu-ala-gly-ser, will they both fold the same? (I think those are d-protein and it's l-protein counterpart)

These are not mirror images, they are entirely different molecules. They are not chiral counterparts (L and D). In general they would not fold to the same structure as the CO and N groups in the backbone are flipped, see more on reddit. However this is a topic of research and some reversable sequences have been found, see Zhang2016 and Mittl2000.

On a deeper level, the researcher's claim that synthesis direction (and hence synthesis broadly) is unimportant is not clear cut. For designed proteins it may be true but these are small and hyperstable. For larger proteins and protein complexes kinetics play more of a role, and chaperones may be used to protect a growing chain as it comes off the ribosome. See for example discussion in Sorokina2018 and Deane2007.