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

Ulmschneider, Jakob P.; Smith, Jeremy C.; White, Stephen H.; Ulmschneider, Martin B.

doi:10.1016/j.bbamem.2018.09.012

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

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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 ΔG_S→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 ΔG_S→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:

Ulmschneider, Jakob P. ^[1];

^[2]; White, Stephen H. ^[3]; Ulmschneider, Martin B. ^[4]

Shanghai Jiao Tong Univ. (China)
Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Univ. of Tennessee, Knoxville, TN (United States)
Univ. of California, Irvine, CA (United States)
King's College London (United Kingdom)

Publication Date:: Thu Sep 20 00:00:00 EDT 2018

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.  doi:10.1016/j.bbamem.2018.09.012.

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                    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

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                    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.

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@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         = {Thu Sep 20 00:00:00 EDT 2018},

  month        = {Thu Sep 20 00:00:00 EDT 2018}

}

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