Origins of the Mechanochemical Coupling of Peptide Bond Formation to Protein Synthesis

Mechanical forces
acting on the ribosome can alter the speed of
protein synthesis, indicating that mechanochemistry can contribute
to translation control of gene expression. The naturally occurring
sources of these mechanical forces, the mechanism by which they are
transmitted 10 nm to the ribosome’s catalytic core, and how
they influence peptide bond formation rates are largely unknown. Here,
we identify a new source of mechanical force acting on the ribosome
by using in situ experimental measurements of changes
in nascent-chain extension in the exit tunnel in conjunction with
all-atom and coarse-grained computer simulations. We demonstrate that
when the number of residues composing a nascent chain increases, its
unstructured segments outside the ribosome exit tunnel generate piconewtons
of force that are fully transmitted to the ribosome’s P-site.
The route of force transmission is shown to be through the nascent
polypetide’s backbone, not through the wall of the ribosome’s
exit tunnel. Utilizing quantum mechanical calculations we find that
a consequence of such a pulling force is to decrease the transition
state free energy barrier to peptide bond formation, indicating that
the elongation of a nascent chain can accelerate translation. Since
nascent protein segments can start out as largely unfolded structural
ensembles, these results suggest a pulling force is present during
protein synthesis that can modulate translation speed. The mechanism
of force transmission we have identified and its consequences for
peptide bond formation should be relevant regardless of the source
of the pulling force.