Dataset Information

Gating gramicidin channels in lipid bilayers: reaction coordinates and the mechanism of dissociation.

ABSTRACT: The dissociation of gramicidin A (gA) channels into monomers is the simplest example of a channel gating process. The initial steps in this process are studied via a computational model that simulates the reaction coordinate for dimer-monomer dissociation. The nonbonded interaction energy between the monomers is determined, allowing for their free relative translational and rotational motion. Lowest energy pathways and reaction coordinates of the gating process are determined. Partial rupture of the six hydrogen bonds (6HB) at the dimer junction takes place by coupling monomer rotation and lateral displacement. Coupling rotation with axial separation is far more expensive energetically. The transition state for channel dissociation occurs when monomers are displaced laterally by approximately 4-6 A, separated by approximately 1.6-2 A, and rotated by approximately 120 degrees, breaking two hydrogen bonds. In membranes with significant hydrophobic mismatch there is a much greater likelihood of forming 4HB and possibly even 2HB states. In the 4HB state the pore remains fully open and conductive. However, transitions from the 6HB to 4HB and 4HB to 2HB states take place via intermediates in which the gA pore is closed and nonconductive. These lateral monomer displacements give rise to transitory pore occlusion at the dimer junction, which provides a rationale for fast closure events (flickers). Local dynamics of gA monomers also leads to lateral and rotational diffusion of the whole gA dimer, giving rise to diffusional rotation of the dimer about the channel axis.

SUBMITTER: Miloshevsky GV

PROVIDER: S-EPMC1303840 | biostudies-literature | 2004 Jan

REPOSITORIES: biostudies-literature

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Gating gramicidin channels in lipid bilayers: reaction coordinates and the mechanism of dissociation.

Miloshevsky Gennady V GV Jordan Peter C PC

Biophysical journal 20040101 1 Pt 1

The dissociation of gramicidin A (gA) channels into monomers is the simplest example of a channel gating process. The initial steps in this process are studied via a computational model that simulates the reaction coordinate for dimer-monomer dissociation. The nonbonded interaction energy between the monomers is determined, allowing for their free relative translational and rotational motion. Lowest energy pathways and reaction coordinates of the gating process are determined. Partial rupture of ...[more]

PMID: 14695253

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Project description:Gramicidin A (gA) is a 15-amino-acid antibiotic peptide with an alternating L-D sequence, which forms (dimeric) bilayer-spanning, monovalent cation channels in biological membranes and synthetic bilayers. We performed molecular dynamics simulations of gA dimers and monomers in all-atom, explicit dilauroylphosphatidylcholine (DLPC), dimyristoylphosphatidylcholine (DMPC), dioleoylphosphatidylcholine (DOPC), and 1-palmitoyl-2-oleoyl-phosphatidylcholine (POPC) bilayers. The variation in acyl chain length among these different phospholipids provides a way to alter gA-bilayer interactions by varying the bilayer hydrophobic thickness, and to determine the influence of hydrophobic mismatch on the structure and dynamics of both gA channels (and monomeric subunits) and the host bilayers. The simulations show that the channel structure varied little with changes in hydrophobic mismatch, and that the lipid bilayer adapts to the bilayer-spanning channel to minimize the exposure of hydrophobic residues. The bilayer thickness, however, did not vary monotonically as a function of radial distance from the channel. In all simulations, there was an initial decrease in thickness within 4-5 Å from the channel, which was followed by an increase in DOPC and POPC or a further decrease in DLPC and DMPC bilayers. The bilayer thickness varied little in the monomer simulations-except one of three independent simulations for DMPC and all three DLPC simulations, where the bilayer thinned to allow a single subunit to form a bilayer-spanning water-permeable pore. The radial dependence of local lipid area and bilayer compressibility is also nonmonotonic in the first shell around gA dimers due to gA-phospholipid interactions and the hydrophobic mismatch. Order parameters, acyl chain dynamics, and diffusion constants also differ between the lipids in the first shell and the bulk. The lipid behaviors in the first shell around gA dimers are more complex than predicted from a simple mismatch model, which has implications for understanding the energetics of membrane protein-lipid interactions.

Project description:Polarizable force fields for lipid and solvent environments are used for molecular dynamics simulations of a fully hydrated dipalmitoylphosphatidylcholine (DPPC) bilayer and gramicidin A (gA) dimer embedded in a dimyristoylphosphatidylcholine (DMPC) bilayer. The lipid bilayer is modeled using the CHARMM charge equilibration (CHEQ) polarizable force field for lipids and the TIP4P-FQ force field to represent solvent. For the DPPC bilayer system, results are compared to the same system simulated using the nonpolarizable CHARMM27r (C27r) force field and TIP3P water. Calculated atomic and electron density profiles, head group orientations as measured by the phosphorus-nitrogen vector orientation, and deuterium order parameters are found to be consistent with previous simulations and with experiment. The CHEQ model exhibits greater water penetration into the bilayer interior, as demonstrated by the potential of mean force calculated from the water density profile. This is a result of the variation of the water molecular dipole from 2.55 D in the bulk to 1.88 D in the interior. We discuss this finding in the context of previous studies (both simulation and experiment) that have investigated the extent of penetration of water into DPPC bilayers. We also discuss the effects of including explicit polarization on the water dipole moment variation as a function of distance from the bilayer. We show distributions of atomic charges over the course of the simulation since the CHEQ model allows the charges to fluctuate. We have calculated the interfacial dipole potential, which the CHEQ model predicts to be 0.95 V compared to 0.86 V as predicted by the C27r model. We also discuss dielectric permittivity profiles and the differences arising between the two models. We obtain bulk values of 72.77 for the CHEQ model (TIP4P-FQ water) and 91.22 for C27r (TIP3P), and values approaching unity in the membrane interior. Finally, we present results of simulations of gA embedded in a DMPC bilayer using the CHEQ model and discuss structural properties.

Dataset Information

Gating gramicidin channels in lipid bilayers: reaction coordinates and the mechanism of dissociation.

Publications

Gating gramicidin channels in lipid bilayers: reaction coordinates and the mechanism of dissociation.

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