The folding of proteins into their native conformation
is a complex
process that has been extensively studied over the past half-century.
The ribosome, the molecular machine responsible for protein synthesis,
is known to interact with nascent proteins, adding further complexity
to the protein folding landscape. Consequently, it is unclear whether
the folding pathways of proteins are conserved on and off the ribosome.
The main question remains: to what extent does the ribosome help proteins
fold? To address this question, we used coarse-grained molecular dynamics
simulations to compare the mechanisms by which the proteins dihydrofolate
reductase, type III chloramphenicol acetyltransferase, andd-alanine–d-alanine ligase B fold during and after
vectorial synthesis on the ribosome to folding from the full-length
unfolded state in bulk solution. Our results reveal that the influence
of the ribosome on protein folding mechanisms varies depending on
the size and complexity of the protein. Specifically, for a small
protein with a simple fold, the ribosome facilitates efficient folding
by helping the nascent protein avoid misfolded conformations. However,
for larger and more complex proteins, the ribosome does not promote
folding and may contribute to the formation of intermediate misfolded
states cotranslationally. These misfolded states persist posttranslationally
and do not convert to the native state during the 6 μs runtime
of our coarse-grain simulations. Overall, our study highlights the
complex interplay between the ribosome and protein folding and provides
insight into the mechanisms of protein folding on and off the ribosome.