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Title: The importance of the membrane interface as the reference state for membrane protein stability

Abstract

The insertion of nascent polypeptide chains into lipid bilayer membranes and the stability of membrane proteins crucially depend on the equilibrium partitioning of polypeptides. For this, the transfer of full sequences of amino-acid residues into the bilayer, rather than individual amino acids, must be understood. Earlier studies have revealed that the most likely reference state for partitioning very hydrophobic sequences is the membrane interface. We have used μs-scale simulations to calculate the interface-to-transmembrane partitioning free energies ΔGS→TM for two hydrophobic carrier sequences in order to estimate the insertion free energy for all 20 amino acid residues when bonded to the center of a partitioning hydrophobic peptide. Our findings reflect that prior single-residue scales likely overestimate the partitioning free energies of polypeptides. The correlation of ΔGS→TM with experimental full-peptide translocon insertion data is high, implying an important role for the membrane interface in translocon-based insertion. The choice of carrier sequence greatly modulates the contribution of each single-residue mutation to the overall partitioning free energy. Our results demonstrate the importance of quantifying the observed full-peptide partitioning equilibrium, which is between membrane interface and transmembrane inserted, rather than combining individual water-to-membrane amino acid transfer free energies.

Authors:
 [1]; ORCiD logo [2];  [3];  [4]
  1. Shanghai Jiao Tong Univ. (China)
  2. Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Univ. of Tennessee, Knoxville, TN (United States)
  3. Univ. of California, Irvine, CA (United States)
  4. King's College London (United Kingdom)
Publication Date:
Research Org.:
Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)
Sponsoring Org.:
USDOE; National Institutes of Health (NIH)
OSTI Identifier:
1561620
Grant/Contract Number:  
AC05-00OR22725
Resource Type:
Accepted Manuscript
Journal Name:
Biochimica et Biophysica Acta. Biomembranes
Additional Journal Information:
Journal Volume: 1860; Journal Issue: 12; Journal ID: ISSN 0005-2736
Publisher:
Elsevier
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; Peptide partitioning; Transfer free energy; Translocon; Membrane; Molecular dynamics

Citation Formats

Ulmschneider, Jakob P., Smith, Jeremy C., White, Stephen H., and Ulmschneider, Martin B. The importance of the membrane interface as the reference state for membrane protein stability. United States: N. p., 2018. Web. https://doi.org/10.1016/j.bbamem.2018.09.012.
Ulmschneider, Jakob P., Smith, Jeremy C., White, Stephen H., & Ulmschneider, Martin B. The importance of the membrane interface as the reference state for membrane protein stability. United States. https://doi.org/10.1016/j.bbamem.2018.09.012
Ulmschneider, Jakob P., Smith, Jeremy C., White, Stephen H., and Ulmschneider, Martin B. Thu . "The importance of the membrane interface as the reference state for membrane protein stability". United States. https://doi.org/10.1016/j.bbamem.2018.09.012. https://www.osti.gov/servlets/purl/1561620.
@article{osti_1561620,
title = {The importance of the membrane interface as the reference state for membrane protein stability},
author = {Ulmschneider, Jakob P. and Smith, Jeremy C. and White, Stephen H. and Ulmschneider, Martin B.},
abstractNote = {The insertion of nascent polypeptide chains into lipid bilayer membranes and the stability of membrane proteins crucially depend on the equilibrium partitioning of polypeptides. For this, the transfer of full sequences of amino-acid residues into the bilayer, rather than individual amino acids, must be understood. Earlier studies have revealed that the most likely reference state for partitioning very hydrophobic sequences is the membrane interface. We have used μs-scale simulations to calculate the interface-to-transmembrane partitioning free energies ΔGS→TM for two hydrophobic carrier sequences in order to estimate the insertion free energy for all 20 amino acid residues when bonded to the center of a partitioning hydrophobic peptide. Our findings reflect that prior single-residue scales likely overestimate the partitioning free energies of polypeptides. The correlation of ΔGS→TM with experimental full-peptide translocon insertion data is high, implying an important role for the membrane interface in translocon-based insertion. The choice of carrier sequence greatly modulates the contribution of each single-residue mutation to the overall partitioning free energy. Our results demonstrate the importance of quantifying the observed full-peptide partitioning equilibrium, which is between membrane interface and transmembrane inserted, rather than combining individual water-to-membrane amino acid transfer free energies.},
doi = {10.1016/j.bbamem.2018.09.012},
journal = {Biochimica et Biophysica Acta. Biomembranes},
number = 12,
volume = 1860,
place = {United States},
year = {2018},
month = {9}
}

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