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Title: Molecular Mechanism for Gramicidin Dimerization and Dissociation in Bilayers of Different Thickness

Abstract

Membrane protein functions can be altered by subtle changes in the host lipid bilayer physical properties. Gramicidin channels have emerged as a powerful system for elucidating the underlying mechanisms of membrane protein function regulation through changes in bilayer properties, which are reflected in the thermodynamic equilibrium distribution between nonconducting gramicidin monomers and conducting bilayer-spanning dimers. To improve our understanding of how subtle changes in bilayer thickness alter the gramicidin monomer and dimer distributions, we performed extensive atomistic molecular dynamics simulations and fluorescence-quenching experiments on gramicidin A (gA). The free-energy calculations predicted a nonlinear coupling between the bilayer thickness and channel formation. The energetic barrier inhibiting gA channel formation was sharply increased in the thickest bilayer (1,2-dierucoyl-sn-glycero-3-phosphocholine). This prediction was corroborated by experimental results on gramicidin channel activity in bilayers of different thickness. To further explore the mechanism of channel formation, we performed extensive unbiased molecular dynamics simulations, which allowed us to observe spontaneous gA dimer formation in lipid bilayers. Here, the simulations revealed structural rearrangements in the gA subunits and changes in lipid packing, as well as water reorganization, that occur during the dimerization process. Together, the simulations and experiments provide new, to our knowledge, insights into the process andmore » mechanism of gramicidin channel formation, as a prototypical example of the bilayer regulation of membrane protein function.« less

Authors:
; ; ; ; ;
Publication Date:
Research Org.:
Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)
Sponsoring Org.:
USDOE National Nuclear Security Administration (NNSA)
OSTI Identifier:
1572725
Alternate Identifier(s):
OSTI ID: 1604286
Report Number(s):
LLNL-JRNL-799526
Journal ID: ISSN 0006-3495; S0006349519308501; PII: S0006349519308501
Grant/Contract Number:  
AC52-07NA27344; R01 GM021342
Resource Type:
Published Article
Journal Name:
Biophysical Journal
Additional Journal Information:
Journal Name: Biophysical Journal Journal Volume: 117 Journal Issue: 10; Journal ID: ISSN 0006-3495
Publisher:
Elsevier
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES

Citation Formats

Sun, Delin, Peyear, Thasin A., Bennett, W. F. Drew, Andersen, Olaf S., Lightstone, Felice C., and Ingólfsson, Helgi I. Molecular Mechanism for Gramicidin Dimerization and Dissociation in Bilayers of Different Thickness. United States: N. p., 2019. Web. doi:10.1016/j.bpj.2019.09.044.
Sun, Delin, Peyear, Thasin A., Bennett, W. F. Drew, Andersen, Olaf S., Lightstone, Felice C., & Ingólfsson, Helgi I. Molecular Mechanism for Gramicidin Dimerization and Dissociation in Bilayers of Different Thickness. United States. doi:https://doi.org/10.1016/j.bpj.2019.09.044
Sun, Delin, Peyear, Thasin A., Bennett, W. F. Drew, Andersen, Olaf S., Lightstone, Felice C., and Ingólfsson, Helgi I. Fri . "Molecular Mechanism for Gramicidin Dimerization and Dissociation in Bilayers of Different Thickness". United States. doi:https://doi.org/10.1016/j.bpj.2019.09.044.
@article{osti_1572725,
title = {Molecular Mechanism for Gramicidin Dimerization and Dissociation in Bilayers of Different Thickness},
author = {Sun, Delin and Peyear, Thasin A. and Bennett, W. F. Drew and Andersen, Olaf S. and Lightstone, Felice C. and Ingólfsson, Helgi I.},
abstractNote = {Membrane protein functions can be altered by subtle changes in the host lipid bilayer physical properties. Gramicidin channels have emerged as a powerful system for elucidating the underlying mechanisms of membrane protein function regulation through changes in bilayer properties, which are reflected in the thermodynamic equilibrium distribution between nonconducting gramicidin monomers and conducting bilayer-spanning dimers. To improve our understanding of how subtle changes in bilayer thickness alter the gramicidin monomer and dimer distributions, we performed extensive atomistic molecular dynamics simulations and fluorescence-quenching experiments on gramicidin A (gA). The free-energy calculations predicted a nonlinear coupling between the bilayer thickness and channel formation. The energetic barrier inhibiting gA channel formation was sharply increased in the thickest bilayer (1,2-dierucoyl-sn-glycero-3-phosphocholine). This prediction was corroborated by experimental results on gramicidin channel activity in bilayers of different thickness. To further explore the mechanism of channel formation, we performed extensive unbiased molecular dynamics simulations, which allowed us to observe spontaneous gA dimer formation in lipid bilayers. Here, the simulations revealed structural rearrangements in the gA subunits and changes in lipid packing, as well as water reorganization, that occur during the dimerization process. Together, the simulations and experiments provide new, to our knowledge, insights into the process and mechanism of gramicidin channel formation, as a prototypical example of the bilayer regulation of membrane protein function.},
doi = {10.1016/j.bpj.2019.09.044},
journal = {Biophysical Journal},
number = 10,
volume = 117,
place = {United States},
year = {2019},
month = {11}
}

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Free Publicly Available Full Text
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DOI: https://doi.org/10.1016/j.bpj.2019.09.044

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