Ribosome Elongation Kinetics of Consecutively Charged Residues Are Coupled to Electrostatic Force

The
speed of protein synthesis can dramatically change when consecutively
charged residues are incorporated into an elongating nascent protein
by the ribosome. The molecular origins of this class of allosteric
coupling remain unknown. We demonstrate, using multiscale simulations,
that positively charged residues generate large forces that move the
P-site amino acid away from the A-site amino acid. Negatively charged
residues generate forces of similar magnitude but move the A- and
P-sites closer together. These conformational changes, respectively,
increase and decrease the transition state barrier height to peptide
bond formation, explaining how charged residues mechanochemically
alter translation speed. This mechanochemical mechanism is consistent
with in vivo ribosome profiling data exhibiting proportionality
between translation speed and the number of charged residues, experimental
data characterizing nascent chain conformations, and a previously
published cryo-EM structure of a ribosome–nascent chain complex
containing consecutive lysines. These results expand the role of mechanochemistry
in translation and provide a framework for interpreting experimental
results on translation speed.