3 research outputs found
Origins of Microstructural Transformations in Charged Vesicle Suspensions: The Crowding Hypothesis
It is observed that
charged unilamellar vesicles in a suspension
can spontaneously deflate and subsequently transition to form bilamellar
vesicles, even in the absence of externally applied triggers such
as salt or temperature gradients. We provide strong evidence that
the driving force for this deflation-induced transition is the repulsive
electrostatic pressure between charged vesicles in concentrated suspensions,
above a critical effective volume fraction. We use volume fraction
measurements and cryogenic transmission electron microscopy imaging
to quantitatively follow both the macroscopic and microstructural
time-evolution of cationic diC18:1 DEEDMAC vesicle suspensions at
different surfactant and salt concentrations. A simple model is developed
to estimate the extent of deflation of unilamellar vesicles caused
by electrostatic interactions with neighboring vesicles. It is determined
that when the effective volume fraction of the suspension exceeds
a critical value, charged vesicles in a suspension can experience
“crowding” due to overlap of their electrical double
layers, which can result in deflation and subsequent microstructural
transformations to reduce the effective volume fraction of the suspension.
Ordinarily in polydisperse colloidal suspensions, particles interacting
via a repulsive potential transform into a glassy state above a critical
volume fraction. The behavior of charged vesicle suspensions reported
in this paper thus represents a new mechanism for the relaxation of
repulsive interactions in crowded situations
Accurate Modeling of Ionic Surfactants at High Concentration
Molecular dynamics (MD) simulation
is a useful tool for simulating
formulations of surfactant mixtures from first-principles, which can
be used to predict surfactant morphology and other industrially relevant
thermodynamic properties. However, the surfactant structure is sensitive
to the parameters used in MD simulations, and in the absence of extensive
validation against experimental data, it is often not obvious <i>a priori</i> which range of parameter sets to choose. In this
work, we compare the performance of ion parameters implemented in
nonpolarizable classical MD simulations, and its effect on simulations
of an idealized solution of sodium dodecyl sulfate (SDS). We find
that previous artifacts reported in simulations of larger SDS constructs
are a direct consequence of using parameters that poorly model ionic
interactions at high concentration. Using osmotic pressure and/or
other thermodynamic properties measured at finite concentration, such
as Kirkwood–Buff integrals, is shown to be the most cost-effective
means to validate and parametrize existing force fields. Our findings
highlight the importance of optimizing intermolecular parameters for
simulations of systems with a high local concentration, which may
be applicable in other contexts, such as in molecular crowding, hotspot
mapping, protein folding, and modeling pH effects
Rationalization of Reduced Penetration of Drugs through Ceramide Gel Phase Membrane
Since computing resources have advanced
enough to allow routine
molecular simulation studies of drug molecules interacting with biologically
relevant membranes, a considerable amount of work has been carried
out with fluid phospholipid systems. However, there is very little
work in the literature on drug interactions with gel phase lipids.
This poses a significant limitation for understanding permeation through
the stratum corneum where the primary pathway is expected to be through
a highly ordered lipid matrix. To address this point, we analyzed
the interactions of <i>p</i>-aminobenzoic acid (PABA) and
its ethyl (benzocaine) and butyl (butamben) esters with two membrane
bilayers, which differ in their fluidity at ambient conditions. We
considered a dioleoylphosphatidylcholine (DOPC) bilayer in a fluid
state and a ceramide 2 (CER2, ceramide NS) bilayer in a gel phase.
We carried out unbiased (100 ns long) and biased <i>z</i>-constraint molecular dynamics simulations and calculated the free
energy profiles of all molecules along the bilayer normal. The free
energy profiles converged significantly slower for the gel phase.
While the compounds have comparable affinities for both membranes,
they exhibit penetration barriers almost 3 times higher in the gel
phase CER2 bilayer. This elevated barrier and slower diffusion in
the CER2 bilayer, which are caused by the high ordering of CER2 lipid
chains, explain the low permeability of the gel phase membranes. We
also compared the free energy profiles from MD simulations with those
obtained from COSMOmic. This method provided the same trends in behavior
for the guest molecules in both bilayers; however, the penetration
barriers calculated by COSMOmic did not differ between membranes.
In conclusion, we show how membrane fluid properties affect the interaction
of drug-like molecules with membranes