19 research outputs found
Permeability of a Fluid Lipid Bilayer to Short-Chain Alcohols from First Principles
Computational
prediction of membrane permeability to small molecules
requires accurate description of both the thermodynamics and kinetics
underlying translocation across the lipid bilayer. In this contribution,
well-converged, microsecond-long free-energy calculations are combined
with a recently developed subdiffusive kinetics framework to describe
the membrane permeation of a homologous series of short-tail alcohols,
from methanol to 1-butanol, with unprecedented fidelity to the underlying
molecular models. While the free-energy profiles exhibit barriers
for passage through the center of the bilayer in all cases, the height
of these barriers decreases with the length of the aliphatic chain
of the alcohol, in quantitative agreement with experimentally determined
differential solvation free energies in water and oil. A unique aspect
of the subdiffusive model employed herein, which was developed in
a previous article, is the determination of a position-dependent fractional
order which quantifies the degree to which the motion of the alcohol
deviates from classical diffusion along the thickness of the membrane.
In the aqueous medium far from the bilayer, this quantity approaches
1.0, the asymptotic limit for purely classical diffusion, whereas
it dips below 0.75 near the center of the membrane irrespective of
the permeant. Remarkably, the fractional diffusivity near the center
of membrane, where its influence on the permeability is the greatest,
is similar among the four permeants despite the large difference in
molecular weight and lipophilicity between methanol and 1-butanol.
The relative permeabilities, which are estimated from the free-energy
and fractional diffusivity profiles, are therefore determined predominantly
by differences in the former rather than the latter. The predicted
relative permeabilities are highly correlated with existing experimental
results, albeit they do not agree quantitatively with them. On the
other hand, quite unexpectedly, the reported experimental values for
the short-tail alcohols are nearly three orders of magnitude lower
than the available experimental measurement for water. Plausible explanations
for this apparent disagreement between theory and experiment are considered
in detail
A high-dimensional neural network potential for molecular dynamics simulations of condensed phase nickel and phase transitions
A high-dimensional neural network interatomic potential was developed and used in molecular dynamics simulations of condensed phase Ni and Ni systems with liquid–solid phase coexistence. The reference data set was generated by sampling the potential energy surface over a broad temperature-pressure domain using ab initio MD simulations to train a unified potential. Excellent agreement was achieved between bulk face-centred cubic nickel thermal expansion simulations and relevant experimental data. The same potential also yields accurate structures and diffusivities in the liquid state. The phase transition between liquid and solid phases was simulated using the two-phase interface method. The predicted melting point temperature is within a few kelvins of the literature value. The general methodology could be applied to describe crystals with much more complex phase behaviours.</p
Iodide Binding in Sodium-Coupled Cotransporters
Several apical iodide translocation
pathways have been proposed
for iodide efflux out of thyroid follicular cells, including a pathway
mediated by the sodium-coupled monocarboxylate transporter 1 (SMCT1),
which remains controversial. Herein, we evaluate structural and functional
similarities between SMCT1 and the well-studied sodium-iodide symporter
(NIS) that mediates the first step of iodide entry into the thyroid.
Free-energy calculations using a force field with electronic polarizability
verify the presence of a conserved iodide-binding pocket between the
TM2, TM3, and TM7 segments in hNIS, where iodide is coordinated by
Phe67, Gln72, Cys91, and Gln94. We demonstrate the mutation of residue
Gly93 of hNIS to a larger amino acid expels the side chain of a critical
tryptophan residue (Trp255) into the interior of the binding pocket,
partially occluding the iodide binding site and reducing iodide affinity,
which is consistent with previous reports associating mutation of
this residue with iodide uptake deficiency and hypothyroidism. Furthermore,
we find that the position of Trp255 in this hNIS mutant mirrors that
of Trp253 in wild-type hSMCT1, where a threonine (Thr91) occupies
the position homologous to that occupied by glycine in wild-type hNIS
(Gly93). Correspondingly, mutation of Thr91 to glycine in hSMCT1 makes
the pocket structure more like that of wild-type hNIS, increasing
its iodide affinity. These results suggest that wild-type hSMCT1 in
the inward-facing conformation may bind iodide only very weakly, which
may have implications for its ability to transport iodide
Diffusive Models of Membrane Permeation with Explicit Orientational Freedom
Accurate
calculation of permeabilities from first-principles has
been a long-standing challenge for computer simulations, notably in
the context of drug discovery, as a route to predict the propensity
of small, organic molecules to spontaneously translocate biological
membranes. Of equal importance is the understanding of the permeation
process and the pathway followed by the permeant from the aqueous
medium to the interior of the lipid bilayer, and back out again. A
convenient framework for the computation of permeabilities is provided
by the solubility–diffusion model, which requires knowledge
of the underlying free-energy and diffusivity landscapes. Here, we
develop a formalism that includes an explicit description of the orientational
motion of the solute as it diffuses across the membrane. Toward this
end, we have generalized a recently proposed method that reconciles
thermodynamics and kinetics in importance-sampling simulations by
means of a Bayesian-inference scheme to reverse-solve the underlying
Smoluchowski equation. Performance of the proposed formalism is examined
in the model cases of a water and an ethanol molecule crossing a fully
hydrated lipid bilayer. Our analysis reveals a conspicuous dependence
of the free-energy and rotational diffusivity on the orientation of
ethanol when it lies within the headgroup region of the bilayer. Specifically,
orientations for which the hydroxyl group lies among the polar lipid
head groups, while the ethyl group recedes toward the hydrophobic
interior are associated with free-energy minima ∼2<i>k</i><sub>B</sub><i>T</i> deep, as well as significantly slower
orientational kinetics compared to the bulk solution or the core of
the bilayer. The conspicuous orientational anisotropy of ethanol at
the aqueous interface is suggestive of a complete rotation of the
permeant as it crosses the hydrophobic interior of the membrane
Calculating Position-Dependent Diffusivity in Biased Molecular Dynamics Simulations
Calculating transition rates and other kinetic quantities
from
molecular simulations requires knowledge not only of the free energy
along the relevant coordinate but also the diffusivity as a function
of that coordinate. A variety of methods are currently used to map
the free-energy landscape in molecular simulations; however, simultaneous
calculation of position-dependent diffusivity is complicated by biasing
forces applied with many of these methods. Here, we describe a method
to calculate position-dependent diffusivities in simulations including
known time-dependent biasing forces, which relies on a previously
proposed Bayesian inference scheme. We first apply the method to an
explicitly diffusive model, and then to an equilibrium molecular dynamics
simulation of liquid water including a position-dependent thermostat,
comparing the results to those of an established method. Finally,
we test the method on a system of liquid water, where oscillations
of the free energy along the coordinate of interest preclude sufficient
sampling in an equilibrium simulation. The adaptive biasing force
method permits roughly uniform sampling along this coordinate, while
the method presented here gives a consistent result for the position-dependent
diffusivity, even in a short simulation where the adaptive biasing
force is only partially converged
Sonoporation at Small and Large Length Scales: Effect of Cavitation Bubble Collapse on Membranes
Ultrasound
has emerged as a promising means to effect controlled
delivery of therapeutic agents through cell membranes. One possible
mechanism that explains the enhanced permeability of lipid bilayers
is the fast contraction of cavitation bubbles produced on the membrane
surface, thereby generating large impulses, which, in turn, enhance
the permeability of the bilayer to small molecules. In the present
contribution, we investigate the collapse of bubbles of different
diameters, using atomistic and coarse-grained molecular dynamics simulations
to calculate the force exerted on the membrane. The total impulse
can be computed rigorously in numerical simulations, revealing a superlinear
dependence of the impulse on the radius of the bubble. The collapse
affects the structure of a nearby immobilized membrane, and leads
to partial membrane invagination and increased water permeation. The
results of the present study are envisioned to help optimize the use
of ultrasound, notably for the delivery of drugs
Water Conduction through a Peptide Nanotube
When inserted into lipid bilayers,
synthetic channels formed by
cyclic peptides of alternated d- and l-α-amino
acids have been shown to modulate the permeability of the cell wall,
thereby endowing them with potential bactericidal capability. Details
of the underlying energetics of the permeation events remain, however,
only fragmentary. Water conduction in a peptide nanotube formed by
eight <i>cyclo</i>-(<u>L</u>W)<sub>4</sub> subunits embedded in a fully hydrated palmitoyloleylphosphatidylcholine
bilayer has been investigated using molecular-dynamics simulations
with a time-dependent bias. The topology of the reconstructed free-energy
landscape delineating the transport of water mirrors the arrangement
of the cyclic peptides in the open-ended tubular structure. Within
the nanotube, the small, periodic free-energy barriers, on the order
of <i>k</i><sub>B</sub><i>T</i>, arising between
adjacent peptide subunits,
are suggestive of unhampered translocation. It still remains that
translational diffusion of water in the hollow cylindrical cavity
is necessarily affected by its interaction with the accessible polar
moieties of the constituent d- and l-α-amino
acids. By combining diffusivity measurements with the free-energy
landscape, we put forth a reaction-rate theory to describe the conduction
kinetics of water inside the peptide nanotube
Assessing Graphene Nanopores for Sequencing DNA
Using all-atom molecular dynamics and atomic-resolution
Brownian
dynamics, we simulate the translocation of single-stranded DNA through
graphene nanopores and characterize the ionic current blockades produced
by DNA nucleotides. We find that transport of single DNA strands through
graphene nanopores may occur in single nucleotide steps. For certain
pore geometries, hydrophobic interactions with the graphene membrane
lead to a dramatic reduction in the conformational fluctuations of
the nucleotides in the nanopores. Furthermore, we show that ionic
current blockades produced by different DNA nucleotides are, in general,
indicative of the nucleotide type, but very sensitive to the orientation
of the nucleotides in the nanopore. Taken together, our simulations
suggest that strand sequencing of DNA by measuring the ionic current
blockades in graphene nanopores may be possible, given that the conformation
of DNA nucleotides in the nanopore can be controlled through precise
engineering of the nanopore surface
Microscopic Perspective on the Adsorption Isotherm of a Heterogeneous Surface
Adsorption of dissolved molecules onto solid surfaces can be extremely sensitive to the atomic-scale properties of the solute and surface, causing difficulties for the design of fluidic systems in industrial, medical, and technological applications. In this communication, we show that the Langmuir isotherm for adsorption of a small molecule to a realistic, heterogeneous surface can be predicted from atomic structures of the molecule and surface through molecular dynamics (MD) simulations. We highlight the method by studying the adsorption of dimethyl methylphosphonate (DMMP) to amorphous silica substrates and show that subtle differences in the atomic-scale surface properties can have drastic effects on the Langmuir isotherm. The sensitivity of the method presented is sufficient to permit the optimization of fluidic devices and to determine fundamental design rules for controlling adsorption at the nanoscale
Assessing Graphene Nanopores for Sequencing DNA
Using all-atom molecular dynamics and atomic-resolution
Brownian
dynamics, we simulate the translocation of single-stranded DNA through
graphene nanopores and characterize the ionic current blockades produced
by DNA nucleotides. We find that transport of single DNA strands through
graphene nanopores may occur in single nucleotide steps. For certain
pore geometries, hydrophobic interactions with the graphene membrane
lead to a dramatic reduction in the conformational fluctuations of
the nucleotides in the nanopores. Furthermore, we show that ionic
current blockades produced by different DNA nucleotides are, in general,
indicative of the nucleotide type, but very sensitive to the orientation
of the nucleotides in the nanopore. Taken together, our simulations
suggest that strand sequencing of DNA by measuring the ionic current
blockades in graphene nanopores may be possible, given that the conformation
of DNA nucleotides in the nanopore can be controlled through precise
engineering of the nanopore surface