European Biophysics Journal

, Volume 46, Issue 7, pp 627–637 | Cite as

Transmembrane helices containing a charged arginine are thermodynamically stable

  • Martin B. Ulmschneider
  • Jakob P. Ulmschneider
  • J. Alfredo Freites
  • Gunnar von Heijne
  • Douglas J. Tobias
  • Stephen H. White
Original Article
  • 579 Downloads

Abstract

Hydrophobic amino acids are abundant in transmembrane (TM) helices of membrane proteins. Charged residues are sparse, apparently due to the unfavorable energetic cost of partitioning charges into nonpolar phases. Nevertheless, conserved arginine residues within TM helices regulate vital functions, such as ion channel voltage gating and integrin receptor inactivation. The energetic cost of arginine in various positions along hydrophobic helices has been controversial. Potential of mean force (PMF) calculations from atomistic molecular dynamics simulations predict very large energetic penalties, while in vitro experiments with Sec61 translocons indicate much smaller penalties, even for arginine in the center of hydrophobic TM helices. Resolution of this conflict has proved difficult, because the in vitro assay utilizes the complex Sec61 translocon, while the PMF calculations rely on the choice of simulation system and reaction coordinate. Here we present the results of computational and experimental studies that permit direct comparison with the Sec61 translocon results. We find that the Sec61 translocon mediates less efficient membrane insertion of Arg-containing TM helices compared with our computational and experimental bilayer-insertion results. In the simulations, a combination of arginine snorkeling, bilayer deformation, and peptide tilting is sufficient to lower the penalty of Arg insertion to an extent such that a hydrophobic TM helix with a central Arg residue readily inserts into a model membrane. Less favorable insertion by the translocon may be due to the decreased fluidity of the endoplasmic reticulum (ER) membrane compared with pure palmitoyloleoyl-phosphocholine (POPC). Nevertheless, our results provide an explanation for the differences between PMF- and experiment-based penalties for Arg burial.

Keywords

Transmembrane helix Arginine Transfer free energy Lipid bilayer membrane Molecular dynamics Sec61 translocon 

Notes

Acknowledgements

This research was supported by a Marie Curie International Fellowship to M.B.U., grants from the National Institute of General Medical Science GM74737 (S.H.W.), Program Project GM86685 from NINDS and NIGMS (S.H.W., D.J.T.), NSF grant CHE-0750175 (D.J.T.), and from the European Research Council (ERC-2008-AdG 232648), the Swedish Cancer Foundation, the Swedish Research Council, and the Swedish Foundation for Strategic Research (G.v.H.).

Supplementary material

249_2017_1206_MOESM1_ESM.pdf (160 kb)
Supplementary material 1 (PDF 159 kb)
249_2017_1206_MOESM2_ESM.doc (552 kb)
Supplementary material 2 (DOC 552 kb)

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Copyright information

© European Biophysical Societies' Association 2017

Authors and Affiliations

  • Martin B. Ulmschneider
    • 1
  • Jakob P. Ulmschneider
    • 2
  • J. Alfredo Freites
    • 3
  • Gunnar von Heijne
    • 4
  • Douglas J. Tobias
    • 3
  • Stephen H. White
    • 5
  1. 1.Institute for NanoBioTechnology and Department of Materials ScienceJohns Hopkins UniversityBaltimoreUSA
  2. 2.Institute of Natural SciencesShanghai Jiao Tong UniversityShanghaiChina
  3. 3.Department of Chemistry and the Center for Biomembrane SystemsUniversity of CaliforniaIrvineUSA
  4. 4.Department of Biochemistry and BiophysicsStockholm UniversityStockholmSweden
  5. 5.Department of Physiology and Biophysics and the Center for Biomembrane SystemsUniversity of CaliforniaIrvineUSA

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