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Free-energy cost for translocon-assisted insertion of membrane proteins.

ABSTRACT: 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 molecular dynamics 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 polyleucine helix. Indeed, the insertion penalty for arginine as well as the insertion gain for leucine from the translocon to the membrane is found to be significantly reduced compared to direct insertion from water, resulting in the same compression as observed in the experiment-based scale.

SUBMITTER: Gumbart J

PROVIDER: S-EPMC3048118 | biostudies-literature | 2011 Mar

REPOSITORIES: biostudies-literature

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Free-energy cost for translocon-assisted insertion of membrane proteins.

Gumbart James J Chipot Christophe C Schulten Klaus K

Proceedings of the National Academy of Sciences of the United States of America 20110211 9

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 argini ...[more]

PMID: 21317362

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Project description:Curvature-sensing and curvature-remodeling proteins, such as Amphiphysin, Epsin, and Exo70, are known to reshape cell membranes, and this remodeling event is essential for key biophysical processes such as tubulation, exocytosis, and endocytosis. Curvature-inducing proteins can act as curvature sensors; they aggregate to membrane regions matching their intrinsic curvature; as well as induce curvature in cell membranes to stabilize emergent high curvature, nonspherical, structures such as tubules, discs, and caveolae. A definitive understanding of the interplay between protein recruitment and migration, the evolution of membrane curvature, and membrane morphological transitions is emerging but remains incomplete. Here, within a continuum framework and using the machinery of Monte Carlo simulations, we introduce and compare three free-energy methods to delineate the free-energy landscape of curvature-inducing proteins on bilayer membranes. We demonstrate the utility of the Widom test particle (or field) insertion methodology in computing the excess chemical potentials associated with curvature-inducing proteins on the membrane-in particular, we use this method to track the onset of morphological transitions in the membrane at elevated protein densities. We validate this approach by comparing the results from the Widom method with those of thermodynamic integration and Bennett acceptance ratio methods. Furthermore, the predictions from the Widom method have been tested against analytical calculations of the excess chemical potential at infinite dilution. Our results are useful in precisely quantifying the free-energy landscape, and also in determining the phase boundaries associated with curvature-induction, curvature-sensing, and morphological transitions. This approach can be extended to studies exploring the role of thermal fluctuations and other external (control) variables, such as membrane excess area, in shaping curvature-mediated interactions on bilayer membranes.

Dataset Information

Free-energy cost for translocon-assisted insertion of membrane proteins.

Publications

Free-energy cost for translocon-assisted insertion of membrane proteins.

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