James Gumbart, Christophe Chipot, and Klaus Schulten.
Free-energy cost for translocon-assisted insertion of membrane
proteins.
Proceedings of the National Academy of Sciences, USA,
108:3596-3601, 2011.
(PMC: PMC3048118)
GUMB2011A
Nascent membrane proteins typically insert in a sequential fashion into the membrane via
a protein-conducting channel, the Sec translocon. How this process occurs is still unclear,
although a thermodynamic partitioning between the channel and the membrane
environment has been proposed. Experiment- and simulation-based scales for the
insertion free energy of various amino acids are, however, at variance, the former
appearing to lie in a narrower range than the latter. Membrane insertion of arginine, for
instance, requires 14-17 kcal/mol according to MD simulations, but only 2-3 kcal/mol
according to experiment. We suggest that this disagreement is resolved by assuming a
two-stage insertion process wherein the first step, the insertion into the translocon, is
energized by protein synthesis and, therefore, has an effectively zero free-energy cost;
the second step, the insertion into the membrane, invokes the translocon as an
intermediary between the fully hydrated and the fully inserted locations. Using free-
energy perturbation calculations, the effective transfer free energies from the translocon
to the membrane have been determined for both arginine and leucine amino acids carried
by a background poly–leucine helix. Indeed, the insertion penalty for arginine as well as
the insertion gain for leucine from the translocon to the membrane are found to be
significantly reduced compared to direct insertion from water, resulting in the same
compression as observed in the experiment-based scale.
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