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Eur Biophys J. 2017 Oct;46(7):627-637. doi: 10.1007/s00249-017-1206-x. Epub 2017 Apr 13.

Transmembrane helices containing a charged arginine are thermodynamically stable.

Author information

1
Institute for NanoBioTechnology and Department of Materials Science, Johns Hopkins University, Baltimore, MD, 21218, USA.
2
Institute of Natural Sciences, Shanghai Jiao Tong University, Shanghai, 200240, China.
3
Department of Chemistry and the Center for Biomembrane Systems, University of California, Irvine, CA, 92697-2025, USA.
4
Department of Biochemistry and Biophysics, Stockholm University, SE-106 91, Stockholm, Sweden.
5
Department of Physiology and Biophysics and the Center for Biomembrane Systems, University of California, Irvine, CA, 92697-4560, USA. stephen.white@uci.edu.

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:

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

PMID:
28409218
PMCID:
PMC5640460
[Available on 2018-10-01]
DOI:
10.1007/s00249-017-1206-x
[Indexed for MEDLINE]

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