7 research outputs found
Input files for "Faster Simulations with a 5 fs Time Step for Lipids in the CHARMM Force Field"
<p>The performance of all-atom molecular dynamics simulations is limited by an integration time step of 2 fs, which is needed to resolve the fastest degrees of freedom in the system, namely, the vibration of bonds and angles involving hydrogen atoms. The virtual interaction sites (VIS) method replaces hydrogen atoms by massless virtual interaction sites to eliminate these degrees of freedom while keeping intact nonbonded interactions and the explicit treatment of hydrogen atoms. We have modified the existing VIS algorithm for most lipids in the popular CHARMM36 force field by increasing the hydrogen atom masses at regular intervals in the lipid acyl chains and obtained lipid properties and pore formation free energies in very good agreement with those calculated in simulations without VIS. Our modified VIS scheme enables a 5 fs time step resulting in a significant performance gain for all-atom simulations of membranes. The method has the potential to make longer time and length scales accessible in all-atom simulations of membrane–protein complexes.</p>
<p>The file set contains individual lipid topologies for virtual interaction sites for standard CHARMM lipids, as well as a README file with instructions on how to implement the VIS algorithm for membranes or membrane-protein complexes</p>
<p>Please Cite:Â <a href="//pubs.acs.org/doi/10.1021/acs.jctc.8b00267">10.1021/acs.jctc.8b00267</a></p>
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Lipid Structure in Triolein Lipid Droplets
Lipid droplets (LDs) are primary
repositories of esterified fatty acids and sterols in animal cells.
These organelles originate on the lumenal or cytoplasmic side of endoplasmic
reticulum (ER) membrane and are released to the cytosol. In contrast
to other intracellular organelles, LDs are composed of a mass of hydrophobic
lipid esters coved by phospholipid monolayer. The small size and unique
architecture of LDs makes it complicated to study LD structure by
modern experimental methods. We discuss coarse-grained molecular dynamics
(MD) simulations of LD formation in systems containing 1-palmitoyl-2-oleoyl-<i>sn</i>-glycero-3-phosphocholine (POPC), 1-palmitoyl-2-oleoyl-<i>sn</i>-glycero-3-phosphoethanolamine (POPE), triolein (TO),
cholesterol (CHOL), and water. We find that (1) there is more cholesterol
in the LD core, than at the interface. (2) No crystallization occurs
inside the LD core. (3) According to coarse-grained simulations, the
presence of PE lipids at the interface has a little impact on distribution
of components and on the overall LD structure. (4) The thickness of
the lipid monolayer at the surface of the droplet is similar to the
thickness of one leaflet of a bilayer. Computer simulations are shown
to be a mighty tool to provide molecular-level insights, which are
not available to the experimental techniques
Accelerating All-Atom MD Simulations of Lipids Using a Modified Virtual-Sites Technique
We present two new implementations
of the virtual sites technique
which completely suppresses the degrees of freedom of the hydrogen
atoms in a lipid bilayer allowing for an increased time step of 5
fs in all-atom simulations of the CHARMM36 force field. One of our
approaches uses the derivation of the virtual sites used in GROMACS
while the other uses a new definition of the virtual sites of the
CH2 groups. Our methods is tested on a DPPC (no unsaturated chain),
a POPC (one unsaturated chain), and a DOPC (two unsaturated chains)
lipid bilayers. We calculate various physical properties of the membrane
of our simulations with and without virtual sites and explain the
differences and similarity observed. The best agreements are obtained
for the GROMACS original virtual sites on the DOPC bilayer where we
get an area per lipid of 67.3 ± 0.3 Å<sup>2</sup> without
virtual sites and 67.6 ± 0.3 Å<sup>2</sup> with virtual
sites. In conclusion the virtual-sites technique on lipid membranes
is a powerful simulation tool, but it should be used with care. The
procedure can be applied to other force fields and lipids in a straightforward
manner
Molecular Mechanism of Na<sup>+</sup>,K<sup>+</sup>‑ATPase Malfunction in Mutations Characteristic of Adrenal Hypertension
Mutations within ion-transporting
proteins may severely affect
their ability to traffic ions properly and thus perturb the delicate
balance of ion gradients. Somatic gain-of-function mutations of the
Na<sup>+</sup>,K<sup>+</sup>-ATPase α1-subunit have been found
in aldosterone-producing adenomas that are among the causes of hypertension.
We used molecular dynamics simulations to investigate the structural
consequences of these mutations, namely, Leu97 substitution by Arg
(L97R), Val325 substitution by Gly (V325G), deletion of residues 93–97
(Del93–97), and deletion–substitution of residues 953–956
by Ser (EETA956S), which shows inward leak currents under physiological
conditions. The first three mutations affect the structural context
of the key ion-binding residue Glu327 at binding site II, which leads
to the loss of the ability to bind ions correctly and to occlude the
pump. The mutated residue in L97R is more hydrated, which ultimately
leads to the observed proton leak. V325G mimics the structural behavior
of L97R; however, it does not promote the hydration of surrounding
residues. In Del93–97, a broader opening is observed because
of the rearrangement of the kinked transmembrane helix 1, M1, which
may explain the sodium leak measured with the mutant. The last mutant,
EETA956S, opens an additional water pathway near the C-terminus, affecting
the III sodium-specific binding site. The results are in excellent
agreement with recent electrophysiology measurements and suggest how
three mutations prevent the occlusion of the Na<sup>+</sup>,K<sup>+</sup>-ATPase, with the possibility of transforming the pump into
a passive ion channel, whereas the fourth mutation provides insight
into the sodium binding in the E1 state
Faster Simulations with a 5 fs Time Step for Lipids in the CHARMM Force Field
The
performance of all-atom molecular dynamics simulations is limited
by an integration time step of 2 fs, which is needed to resolve the
fastest degrees of freedom in the system, namely, the vibration of
bonds and angles involving hydrogen atoms. The virtual interaction
sites (VIS) method replaces hydrogen atoms by massless virtual interaction
sites to eliminate these degrees of freedom while keeping intact nonbonded
interactions and the explicit treatment of hydrogen atoms. We have
modified the existing VIS algorithm for most lipids in the popular
CHARMM36 force field by increasing the hydrogen atom masses at regular
intervals in the lipid acyl chains and obtained lipid properties and
pore formation free energies in very good agreement with those calculated
in simulations without VIS. Our modified VIS scheme enables a 5 fs
time step resulting in a significant performance gain for all-atom
simulations of membranes. The method has the potential to make longer
time and length scales accessible in all-atom simulations of membrane–protein
complexes
Membrane Tubulation in Lipid Vesicles Triggered by the Local Application of Calcium Ions
Experimental and
theoretical studies on ion–lipid interactions
predict that binding of calcium ions to cell membranes leads to macroscopic
mechanical effects and membrane remodeling. Herein, we provide experimental
evidence that a point source of Ca<sup>2+</sup> acting upon a negatively
charged membrane generates spontaneous curvature and triggers the
formation of tubular protrusions that point away from the ion source.
This behavior is rationalized by strong binding of the divalent cations
to the surface of the charged bilayer, which effectively neutralizes
the surface charge density of outer leaflet of the bilayer. The mismatch
in the surface charge density of the two leaflets leads to nonzero
spontaneous curvature. We probe this mismatch through the use of molecular
dynamics simulations and validate that calcium ion binding to a lipid
membrane is sufficient to generate inward spontaneous curvature, bending
the membrane. Additionally, we demonstrate that the formed tubular
protrusions can be translated along the vesicle surface in a controlled
manner by repositioning the site of localized Ca<sup>2+</sup> exposure.
The findings demonstrate lipid membrane remodeling in response to
local chemical gradients and offer potential insights into the cell
membrane behavior under conditions of varying calcium ion concentrations
Membrane Tubulation in Lipid Vesicles Triggered by the Local Application of Calcium Ions
Experimental and
theoretical studies on ion–lipid interactions
predict that binding of calcium ions to cell membranes leads to macroscopic
mechanical effects and membrane remodeling. Herein, we provide experimental
evidence that a point source of Ca<sup>2+</sup> acting upon a negatively
charged membrane generates spontaneous curvature and triggers the
formation of tubular protrusions that point away from the ion source.
This behavior is rationalized by strong binding of the divalent cations
to the surface of the charged bilayer, which effectively neutralizes
the surface charge density of outer leaflet of the bilayer. The mismatch
in the surface charge density of the two leaflets leads to nonzero
spontaneous curvature. We probe this mismatch through the use of molecular
dynamics simulations and validate that calcium ion binding to a lipid
membrane is sufficient to generate inward spontaneous curvature, bending
the membrane. Additionally, we demonstrate that the formed tubular
protrusions can be translated along the vesicle surface in a controlled
manner by repositioning the site of localized Ca<sup>2+</sup> exposure.
The findings demonstrate lipid membrane remodeling in response to
local chemical gradients and offer potential insights into the cell
membrane behavior under conditions of varying calcium ion concentrations