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Transmembrane helices containing a charged arginine are thermodynamically stable
Martin B Ulmschneider1, Jakob P Ulmschneider2, J Alfredo Freites3
1Institute for NanoBioTechnology and Department of Materials Science, Johns Hopkins University, Baltimore, MD, 21218, USA.
European Biophysics Journal : EBJ
|April 15, 2017
Summary
Arginine residues in membrane proteins can insert into hydrophobic environments more easily than previously thought. Computational and experimental studies reveal mechanisms like snorkeling that reduce insertion penalties, resolving a long-standing controversy.
Area of Science:
- Biochemistry
- Molecular Biology
- Biophysics
Background:
- Transmembrane (TM) helices of membrane proteins are rich in hydrophobic amino acids.
- Charged residues, like arginine, are typically sparse in TM helices due to unfavorable partitioning into nonpolar phases.
- Conserved arginine residues in TM helices play crucial roles in protein function, including voltage gating and receptor inactivation.
Purpose of the Study:
- To resolve the controversy surrounding the energetic cost of arginine insertion into hydrophobic membrane environments.
- To directly compare computational and experimental results with those obtained using the Sec61 translocon.
- To investigate the mechanisms underlying arginine insertion into model membranes.
Main Methods:
- Atomistic molecular dynamics simulations using potential of mean force (PMF) calculations.
- In vitro experiments utilizing the Sec61 translocon.
- Bilayer insertion experiments for direct comparison.
Main Results:
- The Sec61 translocon mediates less efficient membrane insertion of arginine-containing TM helices compared to bilayer insertion.
- Computational simulations showed that arginine snorkeling, bilayer deformation, and peptide tilting significantly lower the penalty for arginine insertion.
- A hydrophobic TM helix with a central arginine readily inserts into a model membrane under simulated conditions.
Conclusions:
- The energetic penalty for arginine burial in membranes is lower than predicted by some PMF calculations.
- Differences in membrane fluidity, such as between endoplasmic reticulum (ER) membranes and POPC bilayers, may explain discrepancies between translocon-based and bilayer-based findings.
- The study provides a mechanistic explanation for the varying experimental and computational penalties observed for arginine burial in membrane proteins.