15 research outputs found
Impact of Cholesterol on Voids in Phospholipid Membranes
Free volume pockets or voids are important to many biological processes in
cell membranes. Free volume fluctuations are a prerequisite for diffusion of
lipids and other macromolecules in lipid bilayers. Permeation of small solutes
across a membrane, as well as diffusion of solutes in the membrane interior are
further examples of phenomena where voids and their properties play a central
role. Cholesterol has been suggested to change the structure and function of
membranes by altering their free volume properties. We study the effect of
cholesterol on the properties of voids in dipalmitoylphosphatidylcholine (DPPC)
bilayers by means of atomistic molecular dynamics simulations. We find that an
increasing cholesterol concentration reduces the total amount of free volume in
a bilayer. The effect of cholesterol on individual voids is most prominent in
the region where the steroid ring structures of cholesterol molecules are
located. Here a growing cholesterol content reduces the number of voids,
completely removing voids of the size of a cholesterol molecule. The voids also
become more elongated. The broad orientational distribution of voids observed
in pure DPPC is, with a 30% molar concentration of cholesterol, replaced by a
distribution where orientation along the bilayer normal is favored. Our results
suggest that instead of being uniformly distributed to the whole bilayer, these
effects are localized to the close vicinity of cholesterol molecules
Molecular Dynamics Simulation of Inverse-Phosphocholine Lipids
We
have performed molecular dynamics simulations of lipid bilayers
composed of inverse-phosphatidylcholines (CPe), an analog of phosphatidylcholine
(PC) with the choline group directly bound to the glycerol backbone
and the phosphate group freely protruding into the water phase. Synthetic
phospholipids with the CPe headgroup have been proposed for use as
drug delivery liposomes. Our simulation results show that the CPe
lipids were characterized by a larger area per lipid molecule than
the PC lipids. This can partly explain experimental results that show
a higher permeability of small solutes through the membranes of liposomes
composed of them. Unlike the PC headgroup, the CPe headgroup was found
not to bind sodium ions at the water membrane interface. Both lipid
types were found to bind calcium ions but do not bind potassium ions.
Inversion of the choline group was found to decrease hydration of
the membrane in the carbonyl region of the bilayer as well as hydration
of the choline group. From analyzing the water ordering in our simulation,
we determined that the orientation of the water layer next to the
CPe membrane is effectively inverted with respect to the water ordering
of the PC membrane, possibly affecting interaction with biomembranes
encountered in drug delivery. Due to changes in ion binding, charge
group distribution, and water orientation, the electrostatic potential
profiles across the lipid bilayer of CPe membranes were found to differ
considerably from those of PC membranes. This is a possible explanation
of the experimentally observed changes in the charged solute permeability
Molecular Dynamics Simulation of PEGylated Membranes with Cholesterol: Building Toward the DOXIL Formulation
PEGylation has been used successfully
to increase the circulation
time of drug delivery liposomes by providing an external steric sheath.
In all FDA approved PEGylated drug delivery liposomes, cholesterol
is a key component. In a continuation of our previous work we have
simulated a PEGylated membrane with cholesterol added to the membrane
formulation to determine the effect on membrane structure of the cholesterolāPEG
interaction. We show that, like the case for the liquid crystalline
membrane, PEG enters into the lipid bilayer, however, in a specific
fashion: the PEG winds along the Ī² face of the cholesterol.
Additionally, PEG interferes with the role cholesterol plays in structuring
and compacting the membrane; when the membrane is PEGylated, the area
per lipid increases, rather than decreases, with increasing cholesterol.
Our studies provide mechanistic explanations for existing experimental
results concerning the effect of adding cholesterol to the PEGylated
liposome, including alteration to the liposome compressibility and
permeability, and the possible PEG-induced release of cholesterol
from the membrane
Calcium Assists Dopamine Release by Preventing Aggregation on the Inner Leaflet of Presynaptic Vesicles
In
this study, the dopamineālipid bilayer interactions were probed
with three physiologically relevant ion compositions using atomistic
molecular dynamics simulations and free energy calculations. The in
silico results indicate that calcium is able to decrease significantly
the binding of dopamine to a neutral (zwitterionic) phosphatidylcholine
lipid bilayer model mimicking the inner leaflet of a presynaptic vesicle.
We argue that the observed calcium-induced effect is likely in crucial
role in the neurotransmitter release from the presynaptic vesicles
docked in the active zone of nerve terminals. The inner leaflets of
presynaptic vesicles, which are responsible for releasing neurotransmitters
into the synaptic cleft, are mainly composed of neutral lipids such
as phosphatidylcholine and phosphatidylethanolamine. The neutrality
of the lipid head group region, enhanced by a low pH level, should
limit membrane aggregation of transmitters. In addition, the simulations
suggest that the high calcium levels inside presynaptic vesicles prevent
even the most lipophilic transmitters such as dopamine from adhering
to the inner leaflet surface, thus rendering unhindered neurotransmitter
release feasible
Interaction of Hematoporphyrin with Lipid Membranes
Natural or synthetic porphyrins are being used as photosensitizers
in photodiagnosis (PD) and photodynamic therapy (PDT) of malignancies
and some other diseases. Understanding the interactions between porphyrins
and cell membranes is therefore important to rationalize the uptake
of photosensitizers and their passive transport through cell membranes.
In this study, we consider the properties of hematoporphyrin (Hp),
a well-known photosensitizer for PD and PDT, in the presence of a
1-palmitoyl-2-oleoyl-<i>sn</i>-glycero-3-phosphocholine
(POPC) bilayer that we use as a model system for protein-free cell
membranes. For this purpose, we employed 200 ns atomic-scale molecular
dynamics (MD) simulations for five systems containing the neutral
(Hp<sup>0</sup>) or the dianionic form (Hp<sup>2ā</sup>) of
Hp and the POPC bilayer. MD simulations allowed one to estimate the
position, orientation, and dynamics of Hp molecules inside the membrane.
The dye molecules were found to reside in the phospholipid headgroup
area close to the carbonyl groups of the POPC acyl chains. Their orientations
were dependent on the protonation state of two propionic groups. Hp<sup>2ā</sup> was found to have a lower affinity to enter the membrane
than the neutral form. The dianions, being in the aqueous phase, formed
stable dimers with a strictly determined geometry. Our results fully
supported the experimental data and provide a more detailed molecular-level
description of the interactions of photosensitizers with lipid membranes
How To Tackle the Issues in Free Energy Simulations of Long Amphiphiles Interacting with Lipid Membranes: Convergence and Local Membrane Deformations
One of the great challenges in membrane
biophysics is to find a
means to foster the transport of drugs across complex membrane structures.
In this spirit, we elucidate methodological challenges associated
with free energy computations of complex chainlike molecules across
lipid membranes. As an appropriate standard molecule to this end,
we consider 7-nitrobenz-2-oxa-1,3-diazol-4-yl-labeled fatty amine,
NBD-C<sub><i>n</i></sub>, which is here dealt with as a
homologous series with varying chain lengths. We found the membraneāwater
interface region to be highly sensitive to details in free energy
computations. Despite considerable simulation times, we observed substantial
hysteresis, the cause being the small frequency of insertion/desorption
events of the amphiphileās alkyl chain in the membrane interface.
The hysteresis was most pronounced when the amphiphile was pulled
from water to the membrane and compromised the data that were not
in line with experiments. The subtleties in umbrella sampling for
computing distance along the transition path were also observed to
be potential causes of artifacts. With the PGD (pull geometry distance)
scheme, in which the distance from the molecule was computed to a
reference plane determined by an average over all lipids in the membrane,
we found marked deformations in membrane structure when the amphiphile
was close to the membrane. The deformations were weaker with the PGC
(pull geometry cylinder) method, where the reference plane is chosen
based on lipids that are within a cylinder of radius 1.7 nm from the
amphiphile. Importantly, the free energy results given by PGC were
found to be qualitatively consistent with experimental data, while
the PGD results were not. We conclude that with long amphiphiles there
is reason for concern with regard to computations of their free energy
profiles. The membraneāwater interface is the region where
the greatest care is warranted
Interaction of Hematoporphyrin with Lipid Membranes
Natural or synthetic porphyrins are being used as photosensitizers
in photodiagnosis (PD) and photodynamic therapy (PDT) of malignancies
and some other diseases. Understanding the interactions between porphyrins
and cell membranes is therefore important to rationalize the uptake
of photosensitizers and their passive transport through cell membranes.
In this study, we consider the properties of hematoporphyrin (Hp),
a well-known photosensitizer for PD and PDT, in the presence of a
1-palmitoyl-2-oleoyl-<i>sn</i>-glycero-3-phosphocholine
(POPC) bilayer that we use as a model system for protein-free cell
membranes. For this purpose, we employed 200 ns atomic-scale molecular
dynamics (MD) simulations for five systems containing the neutral
(Hp<sup>0</sup>) or the dianionic form (Hp<sup>2ā</sup>) of
Hp and the POPC bilayer. MD simulations allowed one to estimate the
position, orientation, and dynamics of Hp molecules inside the membrane.
The dye molecules were found to reside in the phospholipid headgroup
area close to the carbonyl groups of the POPC acyl chains. Their orientations
were dependent on the protonation state of two propionic groups. Hp<sup>2ā</sup> was found to have a lower affinity to enter the membrane
than the neutral form. The dianions, being in the aqueous phase, formed
stable dimers with a strictly determined geometry. Our results fully
supported the experimental data and provide a more detailed molecular-level
description of the interactions of photosensitizers with lipid membranes
<i>doGlycans</i>āTools for Preparing Carbohydrate Structures for Atomistic Simulations of Glycoproteins, Glycolipids, and Carbohydrate Polymers for GROMACS
Carbohydrates constitute a structurally
and functionally diverse
group of biological molecules and macromolecules. In cells they are
involved in, e.g., energy storage, signaling, and cellācell
recognition. All of these phenomena take place in atomistic scales,
thus atomistic simulation would be the method of choice to explore
how carbohydrates function. However, the progress in the field is
limited by the lack of appropriate tools for preparing carbohydrate
structures and related topology files for the simulation models. Here
we present tools that fill this gap. Applications where the tools
discussed in this paper are particularly useful include, among others,
the preparation of structures for glycolipids, nanocellulose, and
glycans linked to glycoproteins. The molecular structures and simulation
files generated by the tools are compatible with GROMACS
Dehydroergosterol as an Analogue for Cholesterol: Why It Mimics Cholesterol So Wellīøor Does It?
Although
dehydroergosterol (DHE) is one of the most commonly used
cholesterol (CHOL) reporters, it has remained unclear why it performs
well compared with most other CHOL analogues and what its possible
limitations are. We present a comprehensive study of the properties
of DHE using a combination of time-resolved fluorescence spectroscopy,
quantum-mechanical electronic structure computations, and classical
atomistic molecular dynamics simulations. We first establish that
DHE mimics CHOL behavior, as previous studies have suggested, and
then move on to elucidate and discuss the particular properties that
render DHE so superior. We found that the main reason why DHE mimics
CHOL so well is due to its ability to stand upright in a membrane
in a manner that is almost identical to that of CHOL. The minor difference
in how DHE and CHOL tilt with respect to membrane normal has only
faint effects on structural membrane properties, and even the lateral
pressure profiles of model membranes with CHOL or DHE are almost identical.
These results suggest that the mechanical/elastic effects of DHE on
the function of mechanically sensitive membrane proteins are not substantially
different from those of CHOL. Our study highlights similar dynamical
behavior of CHOL and DHE, which implies that DHE can mimic CHOL in
processes with free energies close to the thermal energy
Effect of PEGylation on Drug Entry into Lipid Bilayer
PolyĀ(ethylene glycol) (PEG) is a
polymer commonly used for functionalization
of drug molecules to increase their bloodstream lifetime, hence efficacy.
However, the interactions between the PEGylated drugs and biomembranes
are not clearly understood. In this study, we employed atomic-scale
molecular dynamics (MD) simulations to consider the behavior of two
drug molecules functionalized with PEG (tetraphenylporphyrin used
in cancer phototherapy and biochanin A belonging to the isoflavone
family) in the presence of a lipid bilayer. The commonly held view
is that functionalization of a drug molecule with a polymer acts as
an entropic barrier, inhibiting the penetration of the drug molecule
through a cell membrane. Our results indicate that in the bloodstream
there is an additional source of electrostatic repulsive interactions
between the PEGylated drugs and the lipid bilayer. Both the PEG chain
and lipids can bind Na<sup>+</sup> ions, thus effectively becoming
positively charged molecules. This leads to an extra repulsive effect
resulting from the presence of salt in the bloodstream. Thus, our
study sheds further light on the role of PEG in drug delivery