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.

doi:10.1016/j.bpj.2019.09.044

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

Journal Article · Fri Nov 01 00:00:00 EDT 2019 · Biophysical Journal

DOI:https://doi.org/10.1016/j.bpj.2019.09.044· OSTI ID:1572725

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

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.

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Research Organization:: Lawrence Livermore National Laboratory (LLNL), Livermore, CA (United States)

Sponsoring Organization:: USDOE National Nuclear Security Administration (NNSA)

Grant/Contract Number:: AC52-07NA27344; R01 GM021342

OSTI ID:: 1572725

Alternate ID(s):: OSTI ID: 1604286

Report Number(s):: LLNL-JRNL-799526; S0006349519308501; PII: S0006349519308501

Journal Information:: Biophysical Journal, Journal Name: Biophysical Journal Vol. 117 Journal Issue: 10; ISSN 0006-3495

Publisher:: ElsevierCopyright Statement

Country of Publication:: United States

Language:: English

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Cited by: 15 works

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