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

Delin Sun, Thasin A. Peyear, W. F.Drew Bennett, Olaf S. Andersen, Felice C. Lightstone, Helgi I. Ingólfsson

Research output: Contribution to journalArticle

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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. 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.

Original languageEnglish (US)
Pages (from-to)1831-1844
Number of pages14
JournalBiophysical Journal
Volume117
Issue number10
DOIs
StatePublished - Nov 19 2019

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Gramicidin
Dimerization
Membrane Proteins
Lipid Bilayers
Molecular Dynamics Simulation
Phosphorylcholine
Thermodynamics
Fluorescence
Lipids

ASJC Scopus subject areas

  • Biophysics

Cite this

Molecular Mechanism for Gramicidin Dimerization and Dissociation in Bilayers of Different Thickness. / Sun, Delin; Peyear, Thasin A.; Bennett, W. F.Drew; Andersen, Olaf S.; Lightstone, Felice C.; Ingólfsson, Helgi I.

In: Biophysical Journal, Vol. 117, No. 10, 19.11.2019, p. 1831-1844.

Research output: Contribution to journalArticle

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. In: Biophysical Journal. 2019 ; Vol. 117, No. 10. pp. 1831-1844.
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