20 research outputs found
On Bilayer Deformation Energetics With and Without Gramicidin A Channel
Lipid membranes are not simply passive barriers. Embedded proteins are coupled to the membrane and can deform the surrounding bilayer, which incurs an energetic penalty. To minimize these penalties, proteins are known to tilt, aggregate, and experience major conformation changes. The degree to which the protein is influenced by the bilayer is dependent on the bilayer material properties and protein-bilayer coupling strength, for example. In this dissertation, the effects of bilayer material properties and protein-bilayer coupling are detailed using gramicidin A channel. This simple channel experiences one major conformational change, its transmembrane dimerization, which produces a bilayer deformation if the bilayer and dimer do not have the same hydrophobic lengths. Herein, molecular dynamics simulations are used to describe bilayer material properties, channel-bilayer coupling, and general lipid energetics with and without gramicidin A
Characterizing Residue-Bilayer Interactions Using Gramicidin A as a Scaffold and Tryptophan Substitutions as Probes
This document is the Accepted Manuscript version of a Published Work that appeared in final form in Journal of Chemical Theory and Computation, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see http://doi.org/10.1021/acs.jctc.7b00400.Previous experiments have shown that the lifetime of a gramicidin A dimer channel (which forms from two non-conducting monomers) in a lipid bilayer is modulated by mutations of the tryptophan (Trp) residues at the bilayer-water interface. We explore this further using extensive molecular dynamics simulations of various gA dimer and monomer mutants at the Trp positions in phosphatidylcholine bilayers with different tail lengths. gA interactions with the surrounding bilayer are strongly modulated by mutating these Trp residues. There are three principal effects: eliminating residue hydrogen bonding ability (i.e., reducing the channel-monolayer coupling strength) reduces the extent of the bilayer deformation caused by the assembled dimeric channel; a residue’s size and geometry affects its orientation, leading to different hydrogen bonding partners; and increasing a residue’s hydrophobicity increases the depth of gA monomer insertion relative to the bilayer center, thereby increasing the lipid bending frustration
Exploring Hydrophobic Mismatch's Impacts on Dissociation of Gramicidin a Channels using Molecular Dynamics Free Energy Simulations
Isolation of histamine-containing cells from rat gastric mucosa: Biochemical and morphologic differences from mast cells
How Tolerant are Membrane Simulations with Mismatch in Area per Lipid between Leaflets?
Difficulties in estimating the correct
number of lipids in each
leaflet of complex bilayer membrane simulation systems make it inevitable
to introduce a mismatch in lipid packing (i.e., area per lipid) and
thus alter the lateral pressure of each leaflet. To investigate potential
impacts of such mismatch on simulation results, we performed molecular
dynamics simulations of saturated and monounsaturated lipid bilayers
with and without gramicidin A or WALP23 at various mismatches by adjusting
the number of lipids in the lower leaflet from no mismatch to a 25%
reduction compared to that in the upper leaflet. All simulations were
stable under the constant pressure barostat, but the mismatch induces
asymmetric lipid packing between the leaflets, so that the upper leaflet
becomes more ordered, and the lower leaflet becomes less ordered.
The mismatch impacts on various bilayer properties are mild up to
5–10% mismatch, and bilayers with fully saturated chains appear
to be more prone to these impacts than those with unsaturated tails.
The nonvanishing leaflet surface tensions and the free energy derivatives
with respect to the bilayer curvature indicate that the bilayer would
be energetically unstable in the presence of mismatch. We propose
a quantitative criterion for allowable mismatch based on the energetics
derived from a continuum elastic model, which grows as a square root
of the number of the lipids in the system. On the basis of this criterion,
we infer that the area per lipid mismatch up to 5% would be tolerable
in various membrane simulations of reasonable all-atom system sizes
(40–160 lipids per leaflet)
All-Atom Simulation and Continuum Elastic Theory of Gramicidin a in Binary Component Lipid Bilayers
Characterizing Residue-Bilayer Interactions Using Gramicidin A as a Scaffold and Tryptophan Substitutions as Probes
Characterizing Residue-Bilayer Interactions Using Gramicidin A as a Scaffold and Tryptophan Substitutions as Probes
Previous
experiments have shown that the lifetime of a gramicidin
A dimer channel (which forms from two nonconducting monomers) in a
lipid bilayer is modulated by mutations of the tryptophan (Trp) residues
at the bilayer-water interface. We explore this further using extensive
molecular dynamics simulations of various gA dimer and monomer mutants
at the Trp positions in phosphatidylcholine bilayers with different
tail lengths. gA interactions with the surrounding bilayer are strongly
modulated by mutating these Trp residues. There are three principal
effects: eliminating residue hydrogen bonding ability (i.e., reducing
the channel-monolayer coupling strength) reduces the extent of the
bilayer deformation caused by the assembled dimeric channel; a residue’s
size and geometry affects its orientation, leading to different hydrogen
bonding partners; and increasing a residue’s hydrophobicity
increases the depth of gA monomer insertion relative to the bilayer
center, thereby increasing the lipid bending frustration