6 research outputs found
Investigating Hydrophilic Pores in Model Lipid Bilayers Using Molecular Simulations: Correlating Bilayer Properties with Pore-Formation Thermodynamics
Cell-penetrating
and antimicrobial peptides show a remarkable ability
to translocate across physiological membranes. Along with factors
such as electric-potential-induced perturbations of membrane structure
and surface tension effects, experiments invoke porelike membrane
configurations during the solute transfer process into vesicles and
cells. The initiation and formation of pores are associated with a
nontrivial free-energy cost, thus necessitating a consideration of
the factors associated with pore formation and the attendant free
energies. Because of experimental and modeling challenges related
to the long time scales of the translocation process, we use umbrella
sampling molecular dynamics simulations with a lipid-density-based
order parameter to investigate membrane-pore-formation free energy
employing Martini coarse-grained models. We investigate structure
and thermodynamic features of the pore in 18 lipids spanning a range
of headgroups, charge states, acyl chain lengths, and saturation.
We probe the dependence of pore-formation barriers on the area per
lipid, lipid bilayer thickness, and membrane bending rigidities in
three different lipid classes. The pore-formation free energy in pure
bilayers and peptide translocating scenarios are significantly coupled
with bilayer thickness. Thicker bilayers require more reversible work
to create pores. The pore-formation free energy is higher in peptide–lipid
systems than in peptide-free lipid systems due to penalties to maintain
the solvation of charged hydrophilic solutes within the membrane environment
Investigating Hydrophilic Pores in Model Lipid Bilayers Using Molecular Simulations: Correlating Bilayer Properties with Pore-Formation Thermodynamics
Cell-penetrating
and antimicrobial peptides show a remarkable ability
to translocate across physiological membranes. Along with factors
such as electric-potential-induced perturbations of membrane structure
and surface tension effects, experiments invoke porelike membrane
configurations during the solute transfer process into vesicles and
cells. The initiation and formation of pores are associated with a
nontrivial free-energy cost, thus necessitating a consideration of
the factors associated with pore formation and the attendant free
energies. Because of experimental and modeling challenges related
to the long time scales of the translocation process, we use umbrella
sampling molecular dynamics simulations with a lipid-density-based
order parameter to investigate membrane-pore-formation free energy
employing Martini coarse-grained models. We investigate structure
and thermodynamic features of the pore in 18 lipids spanning a range
of headgroups, charge states, acyl chain lengths, and saturation.
We probe the dependence of pore-formation barriers on the area per
lipid, lipid bilayer thickness, and membrane bending rigidities in
three different lipid classes. The pore-formation free energy in pure
bilayers and peptide translocating scenarios are significantly coupled
with bilayer thickness. Thicker bilayers require more reversible work
to create pores. The pore-formation free energy is higher in peptide–lipid
systems than in peptide-free lipid systems due to penalties to maintain
the solvation of charged hydrophilic solutes within the membrane environment
Size-Dependent Conformational Features of Aβ<sub>17–42</sub> Protofilaments from Molecular Simulation Studies
Alzheimer’s disease is caused
due to aggregation of amyloid
beta (Aβ) peptide into soluble oligomers and insoluble fibrils
in the brain. In this study, we have performed room temperature molecular
dynamics simulations to probe the size-dependent conformational features
and thermodynamic stabilities of five Aβ<sub>17–42</sub> protofilaments, namely, O<sub>5</sub> (pentamer), O<sub>8</sub> (octamer),
O<sub>10</sub> (decamer), O<sub>12</sub> (dodecamer), and O<sub>14</sub> (tetradecamer). Analysis of the free energy profiles of the aggregates
showed that the higher order protofilaments (O<sub>10</sub>, O<sub>12</sub>, and O<sub>14</sub>) undergo conformational transitions
between two minimum energy states separated by small energy barriers,
while the smaller aggregates (O<sub>5</sub> and O<sub>8</sub>) remain
in single deep minima surrounded by high barriers. Importantly, it
is demonstrated that O<sub>10</sub> is the crossover point for which
the twisting of the protofilament is maximum, beyond which the monomers
tend to rearrange themselves in an intermediate state and eventually
transform into more stable conformations. Our results suggest that
the addition of monomers along the axis of an existing protofilament
with a critical size (O<sub>10</sub> according to the present study)
proceeds via an intermediate step with relatively less stable twisted
structure that allows the additional monomers to bind and form stable
larger protofilaments with minor rearrangements among themselves.
More importantly, it is demonstrated that a combination of twist angle
and end-to-end distance can be used as a suitable reaction coordinate
to describe the growth mechanism of Aβ protofilaments in simulation
studies
Reconciling Structural and Thermodynamic Predictions Using All-Atom and Coarse-Grain Force Fields: The Case of Charged Oligo-Arginine Translocation into DMPC Bilayers
Using the translocation of short,
charged cationic oligo-arginine peptides (mono-, di-, and triarginine)
from bulk aqueous solution into model DMPC bilayers, we explore the
question of the similarity of thermodynamic and structural predictions
obtained from molecular dynamics simulations using all-atom and Martini
coarse-grain force fields. Specifically, we estimate potentials of
mean force associated with translocation using standard all-atom (CHARMM36
lipid) and polarizable and nonpolarizable Martini force fields, as
well as a series of modified Martini-based parameter sets. We find
that we are able to reproduce qualitative features of potentials of
mean force of single amino acid side chain analogues into model bilayers.
In particular, modifications of peptide–water and peptide–membrane
interactions allow prediction of free energy minima at the bilayer–water
interface as obtained with all-atom force fields. In the case of oligo-arginine
peptides, the modified parameter sets predict interfacial free energy
minima as well as free energy barriers in almost quantitative agreement
with all-atom force field based simulations. Interfacial free energy
minima predicted by a modified coarse-grained parameter set are −2.51,
−4.28, and −5.42 for mono-, di-, and triarginine; corresponding
values from all-atom simulations are −0.83, −3.33, and
−3.29, respectively, all in units of kcal/mol. We found that
a stronger interaction between oligo-arginine and the membrane components
and a weaker interaction between oligo-arginine and water are crucial
for producing such minima in PMFs using the polarizable CG model.
The difference between bulk aqueous and bilayer center states predicted
by the modified coarse-grain force field are 11.71, 14.14, and 16.53
kcal/mol, and those by the all-atom model are 6.94, 8.64, and 12.80
kcal/mol; those are of almost the same order of magnitude. Our simulations
also demonstrate a remarkable similarity in the structural aspects
of the ensemble of configurations generated using the all-atom and
coarse-grain force fields. Both resolutions show that oligo-arginine
peptides adopt preferential orientations as they translocate into
the bilayer. The guiding theme centers on charged groups maintaining
coordination with polar and charged bilayer components as well as
local water. We also observe similar behaviors related with membrane
deformations
Investigating Hydrophilic Pores in Model Lipid Bilayers Using Molecular Simulations: Correlating Bilayer Properties with Pore-Formation Thermodynamics
Cell-penetrating
and antimicrobial peptides show a remarkable ability
to translocate across physiological membranes. Along with factors
such as electric-potential-induced perturbations of membrane structure
and surface tension effects, experiments invoke porelike membrane
configurations during the solute transfer process into vesicles and
cells. The initiation and formation of pores are associated with a
nontrivial free-energy cost, thus necessitating a consideration of
the factors associated with pore formation and the attendant free
energies. Because of experimental and modeling challenges related
to the long time scales of the translocation process, we use umbrella
sampling molecular dynamics simulations with a lipid-density-based
order parameter to investigate membrane-pore-formation free energy
employing Martini coarse-grained models. We investigate structure
and thermodynamic features of the pore in 18 lipids spanning a range
of headgroups, charge states, acyl chain lengths, and saturation.
We probe the dependence of pore-formation barriers on the area per
lipid, lipid bilayer thickness, and membrane bending rigidities in
three different lipid classes. The pore-formation free energy in pure
bilayers and peptide translocating scenarios are significantly coupled
with bilayer thickness. Thicker bilayers require more reversible work
to create pores. The pore-formation free energy is higher in peptide–lipid
systems than in peptide-free lipid systems due to penalties to maintain
the solvation of charged hydrophilic solutes within the membrane environment
Translocation Thermodynamics of Linear and Cyclic Nonaarginine into Model DPPC Bilayer via Coarse-Grained Molecular Dynamics Simulation: Implications of Pore Formation and Nonadditivity
Structural mechanisms
and underlying thermodynamic determinants
of efficient internalization of charged cationic peptides (cell-penetrating
peptides, CPPs) such as TAT, polyarginine, and their variants, into
cells, cellular constructs, and model membrane/lipid bilayers (large
and giant unilamellar or multilamelar vesicles) continue to garner
significant attention. Two widely held views on the translocation
mechanism center on endocytotic and nonendocytotic (diffusive) processes.
Espousing the view of a purely diffusive internalization process (supported
by recent experimental evidence, [Säälik, P.; et al. <i>J. Controlled Release</i> <b>2011</b>, <i>153</i>, 117–125]), we consider the underlying free energetics of
the translocation of a nonaarginine peptide (Arg<sub>9</sub>) into
a model DPPC bilayer. In the case of the Arg<sub>9</sub> cationic
peptide, recent experiments indicate a higher internalization efficiency
of the cyclic structure (cyclic Arg<sub>9</sub>) relative to the linear
conformer. Furthermore, recent all-atom resolution molecular dynamics
simulations of cyclic Arg<sub>9</sub> [Huang, K.; et al. <i>Biophys.
J.</i>, <b>2013</b>, <i>104</i>, 412–420]
suggested a critical stabilizing role of water- and lipid-constituted
pores that form within the bilayer as the charged Arg<sub>9</sub> translocates
deep into the bilayer center. Herein, we use umbrella sampling molecular
dynamics simulations with coarse-grained Martini lipids, polarizable
coarse-grained water, and peptide to explore the dependence of translocation
free energetics on peptide structure and conformation via calculation
of potentials of mean force along preselected reaction paths allowing
and preventing membrane deformations that lead to pore formation.
Within the context of the coarse-grained force fields we employ, we
observe significant barriers for Arg<sub>9</sub> translocation from
bulk aqueous solution to bilayer center. Moreover, we do not find
free-energy minima in the headgroup–water interfacial region,
as observed in simulations using all-atom force fields. The pore-forming
paths systematically predict lower free-energy barriers (ca. 90 kJ/mol
lower) than the non pore-forming paths, again consistent with all-atom
force field simulations. The current force field suggests no preference
for the more compact or covalently cyclic structures upon entering
the bilayer. Decomposition of the PMF into the system’s components
indicates that the dominant stabilizing contribution along the pore-forming
path originates from the membrane as both layers of it deformed due
to the formation of pore. Furthermore, our analysis revealed that
although there is significant entropic stabilization arising from
the enhanced configurational entropy exposing more states as the peptide
moves through the bilayer, the enthalpic loss (as predicted by the
interactions of this coarse-grained model) far outweighs any former
stabilization, thus leading to significant barrier to translocation.
Finally, we observe reduction in the translocation free-energy barrier
for a second Arg<sub>9</sub> entering the bilayer in the presence
of an initial peptide restrained at the center, again, in qualitative
agreement with all-atom force fields