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Article
Cite This: ACS Omega 2019, 4, 11066−11073
http://pubs.acs.org/journal/acsodf
C‑Terminal Plays as the Possible Nucleation of the Self-Aggregation
of the S‑Shape Aβ11−42 Tetramer in Solution: Intensive MD Study
Nguyen Thanh Tung,† Philippe Derreumaux,‡,§,∥ Van V. Vu,⊥ Pham Cam Nam,#
and Son Tung Ngo*,¶,∇
†
Institute of Materials Science, Vietnam Academy of Science and Technology, Hanoi 10307, Vietnam
Laboratory of Theoretical and Chemistry, Ton Duc Thang University, Ho Chi Minh City 758307, Vietnam
§
Faculty of Pharmacy, Ton Duc Thang University, Ho Chi Minh City 758307, Vietnam
∥
Laboratoire de Biochimie Theorique, UPR 9080 CNRS, IBPC, Universite Paris 7, 13 rue Pierre et Marie Curie, 75005 Paris, France
⊥
NTT Hi-Tech Institute, Nguyen Tat Thanh University, Ho Chi Minh City 70000, Vietnam
#
Department of Chemical Engineering, The University of Da NangUniversity of Science and Technology, Da Nang City 550000,
Vietnam
¶
Laboratory of Theoretical and Computational Biophysics, Ton Duc Thang University, Ho Chi Minh City 758307, Vietnam
∇
Faculty of Applied Sciences, Ton Duc Thang University, Ho Chi Minh City 758307, Vietnam
Downloaded by 42.118.12.28 at 08:04:07:483 on June 26, 2019
from https://pubs.acs.org/doi/10.1021/acsomega.9b00992.
‡
S Supporting Information
*
ABSTRACT: Amyloid beta (Aβ) peptides are characterized
as the major factors associated with neuron death in
Alzheimer’s disease, which is listed as the most common
form of neurodegeneration. Disordered Aβ peptides are
released from proteolysis of the amyloid precursor protein.
The Aβ self-assembly process roughly takes place via five
steps: disordered forms → oligomers → photofibrils →
mature fibrils → plaques. Although Aβ fibrils are often
observed in patient brains, oligomers were recently indicated
to be major neurotoxic elements. In this work, the neurotoxic
compound S-shape Aβ11−42 tetramer (S4Aβ11−42) was
investigated over 10 μs of unbiased MD simulations. In
particular, the S4Aβ11−42 oligomer adopted a high dynamics
structure, resulting in unsuccessful determination of their structures in experiments. The C-terminal was suggested as the
possible nucleation of the Aβ42 aggregation. The sequences 27−35 and 39−40 formed rich β-content, whereas other residues
mostly adopted coil structures. The mean value of the β-content over the equilibrium interval is ∼42 ± 3%. Furthermore, the
dissociation free energy of the S4Aβ11−42 peptide was predicted using a biased sampling method. The obtained free energy is
ΔGUS = −58.44 kcal/mol which is roughly the same level as the corresponding value of the U-shape Aβ17‑42 peptide. We
anticipate that the obtained S4Aβ11−42 structures could be used as targets for AD inhibitor screening over the in silico study.
■
INTRODUCTION
Missing knowledge of the stable structures of Aβ oligomers
has hindered their functional studies,11,12 resulting in
unsuccessful designing of inhibitors for Aβ oligomers to date.
In the case of distinguished Aβ oligomers, it is popularly
argued that the β-strand content is related to neurotoxicity.13
Promising inhibitors for the Aβ oligomerization mostly focus
on preventing the β-structure.14,15 Although these compounds
are able to inhibit Aβ oligomerization in both experimental and
computational studies,16 the number of available drugs is
negligible unfortunately.17 Moreover, some compounds, which
are able to enhance the self-assembly rate of Aβ peptides, have
Alzheimer’s disease (AD) is known as common dementia,
affecting more than 40 million people worldwide.1 AD patients
lose cognition and memory slowly for more than 20 years
before the symptoms are clarified.2,3 Among several hypotheses
which have been proposed to explain the mechanism of AD,
the amyloid cascade hypothesis emerges as one of the most
probable ones. In particular, AD is associated with the aspect
of Amyloid beta (Aβ) oligomers.4,5 Thus, understanding the
structure of Aβ oligomers at the atomic level might enhance
AD therapy.6,7 Unfortunately, it is very hard to identify
structural details of oligomers in experiments because they
exist transiently.8 Computational investigations thus emerged
as a highly appropriate method to resolve these problems.9,10
© 2019 American Chemical Society
Received: April 8, 2019
Accepted: May 27, 2019
Published: June 25, 2019
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also been used as potential inhibitors.18,19 If the lag phase time
of Aβ oligomerization is decreased, the oligomeric period
would thus be reduced. However, efficient compounds are still
obstacles despite much effort over recent years.5,19
It is known that the self-aggregation of Aβ peptides strongly
rely upon their sequences and fragment sizes.20,21 Mutations
are able to change the structure and kinetics of Aβ oligomers
such as A2T,22 A2V,22 D7N,23 F19W,24 A21G,25 E22G,26
E22Q,27,28 E22K,26 and D23N29,30 mutations. The familial
mutations attract several investigations due to their influence
on AD patients. Moreover, the chain length absolutely alters
the self-assembly rate and kinetics of Aβ peptides. The
fibrillation time of the more common Aβ40 peptide is
significantly larger than that of the Aβ42 peptide,31 although
there are two residue differences only.6 However, it is very hard
to characterize the structural information of Aβ42 oligomers in
solution,8,32 because the more toxic Aβ42 oligomers are more
unstable than the Aβ40 ones.32 Furthermore, the lag phase of
the Aβ peptide also depends on the order/weight of the
oligomer.21,33 The higher-order oligomer requires a larger selfaggregation time.33
In addition, due to the fact that Aβ trimers and tetramers are
the highest cytotoxicity forms of low-weight oligomers,34 many
investigations were implemented to understand the structural
information of Aβ trimers.30,35−38 However, detailed information of Aβ tetramers is still limited, especially the structural
details of Aβ42 tetramers because these oligomers are highly
dynamic compounds.32 Despite efforts to mimic the formation
of the solvated Aβ1‑42 tetramer starting from Aβ1‑42 monomers
using discrete MD simulations,39 the β-content of the obtained
Aβ1‑42 tetramer (<18%) was found to be significantly lower
than the experimental observations.40 Moreover, the Aβ1‑42
tetramer with the appropriate amount of β-content (34 ± 5%)
was also formed from 4 Aβ1‑42 monomers using MD
simulations,41 but it is hard to explain the elongation of Aβ
photofibrils based on the morphology of the obtained Aβ1‑42
tetramer, which is considered as subunits constructing the
fibrils.31,42−44 Therefore, an investigation for the formation of
the Aβ tetramer emerges as an urgent task, in which the
obtained structures would satisfy critical conditions such as
adopting appropriate oligomeric size, suitable secondary
structures, and the ability to be used as subunits for elongating
photofibrils.
In this work, we have simulated Aβ11−42 tetramer starting
from the fibril-like S-shape structure (S4Aβ11−42) over 10 μs of
MD simulations to understand the structural change of this
compound in solution. The representative shapes of the
S4Aβ11−42 peptide are obtained using a combination of the
collective-variable free energy landscape (FEL) and clustering
methods according to previous works.30,45 The secondary
structure change of the peptide was monitored every 10 ps
employing the dictionary of protein secondary structure
(DSSP) protocol.46 The oligomer size fluctuation was
observed over the radius of gyration, collision cross section
(CCS), and solvent surface accessible area (SASA) calculations. The obtained results would enhance the understanding
of the Aβ self-aggregation.
simulations, whereas the initial structures are able to be a
random coil39,41 or a fibril-like structure.10,48 There is a
prohibition of CPU time consumption for simulating the
disordered protein which is started from a random structure
initially.10 Moreover, although the disordered domain with a
sequence of 1−10 was found to be able to alter the selfaggregation of Aβ oligomers,22,23 these effects are insignificant
in comparison with those of the hydrophobic domains. The
sequence has frequently not been included in previous
studies.49−52 Inconsideration of the disordered domain also
provides the advantage that the CPU time consumption would
reduce.30 Furthermore, the Aβ peptides normally adopt
monomorphic,52 two-fold,53,54 and three-fold structures.55
However, the computational study of the two-fold and threefold shapes would be much more time consuming because of
extremely increasing the degree of freedom in comparison with
the monomorphic system. Therefore, a fibril-like structure of
the Aβ11−42 peptide with a monomorphic conformation would
be selected as the initial structure of a long time scale MD
simulation, which is known to be able to appropriately sample
the conformation of the Aβ peptide.56 Here, the S-shape
model52 was chosen as the investigated model instead of the
U-shape model.57 The initial shape of S-shape Aβ11−42 is
shown in Figure 1.
Figure 1. Initial conformation of the S4Aβ11−42 peptide, which was
extracted from the S-shape Aβ11−42 fibril with PDB ID 2MXU.52 The
blue spheres were employed to note the N-terminus.
All-Atom Molecular Dynamics Simulation. A long time
conventional MD simulation would provide details of both
dynamics and kinetics of the Aβ self-aggregation process.
During the simulations, the tetramer significantly adopts the
structural changes over the first 4 μs of MD simulation until
reaching a stable point (Figure S1 of the Supporting
Information). The convergence of simulations was guaranteed
according the superposition of the calculated metrics over
various simulation time intervals (Figure S2). The structural
analyses were thus performed over the time interval 4−10 μs of
MD simulations. During the equilibrium interval, the Cα
atomic fluctuations (Figure S3 of the Supporting Information
file) indicated that the sequences 15−20 and 24−37 are rigidly
stable during simulation with a Cα RMSF of approximately
0.14 nm, while sequences 11−14, 21−23, and 38−42 change
with a Cα RMSF ranging from 0.20 to 0.5 nm. The obtained
results are in good agreement with the secondary structure
■
RESULTS AND DISCUSSION
Selected Initial Conformation of the Aβ Tetramer. Aβ
oligomers are probable establishing blocks for generating
photofibrils and/or mature fibrils.10,47 It may be argued that
the shapes of Aβ oligomers might be collected from the
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CCS, SASA, and number of SC implied the high dynamics of
the S4Aβ11−42 system according to the previous observation.32
Secondary Structure of the S4Aβ11−42. Secondary
structures are important metrics characterizing physical and
structural properties of Aβ systems. Normally, the β-content of
Aβ peptides is supposedly related to the neurotoxicity of the
oligomers because the value is characterizing the self-assembly
of Aβ peptides.32 The secondary structure changes were
monitored employing the DSSP protocol over the time interval
4−10 μs of MD simulations.46 The obtained distributions of
the secondary structure values are mentioned in Figure 3. In
analysis in the next subsection. The C-terminal is more
important than the N-terminal stabilizing the S4Aβ11−42
oligomer. It implies that the C-terminal enables possible
nucleation of the S4Aβ11−42 self-assembly instead of the Nterminal, which controls the aggregation of the 3Aβ11‑40
peptide.10 Furthermore, it may be argued that available
inhibitors for the Aβ40 peptide would have less effect on the
Aβ42 peptides because these compounds favorably bind to the
N-terminal.30
In addition, the dynamics of the S4Aβ11−42 peptide was a
probable interpretation through monitoring the system size
and intermolecular interactions between the constituting
chains (Figure 2). The obtained size of the S4Aβ11−42 peptide
Figure 3. Distributions of secondary structure terms of the S4Aβ11−42
peptide over the last 6 μs of MD simulations.
Figure 2. Computed metrics of the S4Aβ11−42 peptide. Collected
metrics were obtained over interval 4−10 μs of MD simulations.
particular, the β-content of the S4Aβ11−42 peptide spreads out
in the range of 24−55% with an average value of 42 ± 3%. The
coil content fluctuates in the range of 37−70% with a mean
amount of 51 ± 3%. The α-content is the smallest amount in
comparison with the other secondary structure terms with the
average amount of 3 ± 2%. The turn content is approximately
measured as 5 ± 2%.
The secondary structure terms per residues of the S4Aβ11−42
peptide were averaged over 600 000 MD snapshots and are
presented in Figure 4. The S4Aβ11−42 system adopts a rigid β-
is appropriate when compared with other oligomers. In
particular, the radius of gyration (Rg) of the S4Aβ11−42 system
was computed with a mean value of 1.46 ± 0.03 nm, which is
significantly smaller than that of the 4Aβ1‑42 peptide in solution
(∼1.6 ± 1 nm).41 The smaller Rg of the S4Aβ11−42 peptide is
probably caused by the shorter of the sequence. However,
interestingly, the Rg value of S4Aβ11−42 is slightly smaller than
that of D23N 3Aβ11‑40 (∼1.49 ± 0.05 nm),30 although the
trimeric system has inevitably fewer number of residues.
Moreover, the Rg value of S4Aβ11−42 spreads out in the larger
range (from 1.38 to 1.78 nm) in comparison with the D23N
3Aβ11‑40 oligomer (from 1.28 to 1.64 nm). The results imply
that the S4Aβ11−42 peptide is more flexible than the D23N
3Aβ11‑40 peptide. On the other hand, the size of the oligomer is
also described through the CCS and SASA values. These
amounts propagate in the large ranges of 14.80−17.60 nm2 and
68.50−87.50 nm2, respectively. The corresponding mean
values are 16.06 ± 0.32 nm2 and 77.23 ± 2.26 nm2,
respectively. The CCS value of the S4Aβ11−42 peptide is
smaller than that of the helical transmembrane Aβ11−42
tetramer (4tmαAβ11−42), which was measured to be 17.64 ±
0.97 nm2.58 Moreover, both CCS and SASA values are
significantly larger than that of Aβ 1 1 ‑ 4 0 trimers
(3Aβ11‑40),10,24,30 although these radii of gyration were
approximately equaled. In addition, the number of intermolecular sidechain contact (SC) between constituting chains of
the S4Aβ11−42 oligomer during the last 6 μs of MD simulations
was counted as 54.98 ± 1.91 that metric was recorded in the
range from 46.50 to 63.00. Overall, the high fluctuations of Rg,
Figure 4. Secondary structure terms per residues of the S4Aβ11−42
peptide over time interval 4−10 μs of MD simulations.
content in the C-terminal (especially in the sequences 27−35
and 39−40). Other residues mostly form the coil structure
implying that the S4Aβ11−42 peptide is highly flexible, which is
in good concurrence with the previous experiment.32
Secondary structure allocation is in good agreement with the
previous studies of the Aβ 1‑42 monomer, dimer, and
pentamer.59−61 On the other hand, the S4Aβ11−42 peptide
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shapes B and C, whereas the structure was not detected in the
representative conformation A (Figure 5). Moreover, it is
known that the self-assembly of the Aβ peptide is supposed to
be random coil structure → α-structure → β-structure.12,62 It
probably can be argued that the similar α-structure
accommodating but richer coil content shape B is an
intermediate structure of the self-assembly process from a
random structure to the shape C. Similarly, the shape C is a
transitional structure of the self-aggregation process from the
α-structure containing the B shape to the metastable shape A.
In other words, the self-assembly pathway would probably be
as follows shape B → shape C → shape A (Figure S4 of
Supporting Information file). This argument is consistent with
the obtained free energy barrier of these conformations (Figure
5).
Dissociation Free Energy of the S4Aβ11‑40 Oligomer.
As mentioned above, the Aβ peptides consisting of three/four
monomers are hallmarked as the most toxic compounds
among low weight oligomers.34 The self-aggregation process
from a trimer to a tetramer could be deduced through studying
the dissociation free energy of the monomer located at the
edge of the Aβ tetramer. The understanding of Aβ selfassembly would be further illuminated. Several approaches
were developed to determine the binding affinity between the
two molecules.63−67 Here, the umbrella sampling (US)
method was employed to estimate the disassociation energy
barrier referring to a previous study.68 The free energy ΔG
over US simulations along reaction coordinate ξ was
determined employing the weight histogram analysis method
(WHAM).69 In particular, the most representative conformation A was chosen to evaluate the dissociation free energy
because its population occupies 56% of the whole considered
MD snapshots. The SMD simulations were carried out to
unbind the Aβ trimer (chain A, B, and C) from the monomer
(chain D) as the modeling is shown in Figure 6, in which we
have assumed that the peptide is roughly symmetrical over the
unbinding direction.68
plays a different role in comparison to the 3Aβ11‑40 oligomer,
which forms a richer β-content in the N-terminal.10 Especially,
the hydrophobic domain of the N-terminal (sequence 17−21)
of the S4Aβ11−42 oligomer forms less than 50% of the βcontent for each residue in comparison with the corresponding
value ∼90% of the U-shape 3Aβ11‑40 peptide.30 It may be
argued that the C-terminal acts as the possible nucleation of
Aβ42 fibrils instead of the N-terminal does in the Aβ40
peptide.10
Representative Structures of the S4Aβ11−42 Peptides.
A combination of the FEL and clustering methods was
employed to find the appropriately representative conformations of the S4Aβ11−42 peptide.45 As mentioned below, the
collective variable FEL was constructed using the backbone
root-mean square deviation (rmsd) and intermolecular SC as
the two reaction coordinates. The S4Aβ11−42 FEL is shown in
Figure 5. Three minima were observed which correspond to
Figure 5. The collective variable free energy landscape of the
S4Aβ11−42 peptide. The backbone rmsd and the mean nonbonded
contacts between the constituting chains of the peptide are used as
the reaction coordinates. The blue spheres were used to denote the
N-terminus.
the coordinates (rmsd; number of SC) of three minima which
are (0.86; 54.75), (0.77; 56.00), and (0.73; 57.50),
respectively. A clustering method with a backbone cut-off 0.2
nm was then applied to the refined snapshots, which was
detected in the free-energy minima, to achieve the
representative shapes of the S4Aβ11−42 peptide. The collected
conformations are noted as A, B, and C as displayed in Figure
5. In particular, these shapes were observed at the
corresponding times as follow 8997.87, 4720.38, and 6008.80
ns, respectively. Furthermore, the corresponding shapes
occupied 56, 7, and 8% of total conformations over the time
interval 4−10 μs of MD simulations. Structural information of
these shapes is described in Table 1. The CCS of the three
shapes is ∼15.88 nm2, which is slightly smaller than that of the
helical transmembrane Aβ17‑42 tetramer (4tmαAβ11−42) with a
value of ∼16.5 nm2.58 The α-content was observed in both
Figure 6. The modeling of the dissociation process of the Aβ trimer
(chain A, B, and C) and monomer (chain D) using SMD simulations.
The pulling force was put on the trimer center of mass shown as the
red arrow. The blue spheres mentioned the N-terminus of the Aβ
peptides.
Table 1. Structural Information of the S4Aβ11−42 Peptidea
structure α (%)
A
B
C
0
1
1
β (%)
turn
(%)
coil
(%)
CCS
(nm2)
population
(%)
43
40
43
5
7
8
52
52
48
15.96
15.71
15.97
56
7
8
During SMD simulations, the Aβ trimer was rapidly forced
to dissociate from chain D. Interestingly, although the pulling
force was put on the center of mass of the trimer, the Cterminal mobilized slower than the N-terminal during the
dissociation process (Figure 6). Observations indicated that
the C-terminal adopts a stronger affinity to the corresponding
domain of other chains in comparison with the N-terminal.
The obtained results are in good agreement with the above
a
Measured values were obtained using DSSP and IMPACT tools.
Backbone rmsd cut-off = 0.2 nm.
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difficulty in determining the oligomeric structures of Aβ42
peptides in experiments.8 It was suggested that the C-terminal
enables possible nucleation in the self-assembly of the Aβ42
peptides. Moreover, the size of the U-shape tetramer is smaller
than that of the 4tmαAβ17‑42 because of 10% of CCS smaller.
Over the secondary structure analysis, C-terminal involving
sequences 27−35 and 39−40 adopt rigid β-content, whereas
other residues including the hydrophobic domain of the Nterminal (sequence 17−21) mostly adopt coil structures. The
self-assembly of the tetramer was assumed due to the collective
variable free energy landscape analysis that involves the selfaggregation pathway as shape B → shape C → shape A. The
conformation A is a metastable structure, observing with the
population of 56%. This shape adopts 43% of β-content.
Furthermore, on the assumption that the system is symmetrical
over the unbinding direction (Figure 6), the dissociation free
energy evaluation of the S4Aβ11−42 peptide was characterized
using US simulations. The obtained ΔGUS of S4Aβ11−42 is
approximately the same as that of the U-shape Aβ17‑42.68 Thus,
the S4Aβ11−42 oligomer probably stabilizes like the U-shape
Aβ17‑42 peptide. We anticipate that the realized S4Aβ11−42
structures could be used as targets for AD inhibitor screening
in silico.
structural analyses. Furthermore, it is implied that the Cterminal is the probable nucleation of the Aβ42 oligomers
instead of the N-terminal in the Aβ40 systems.30
The coordinates of the whole system were monitored every
∼0.1 nm such that they would be served as the initial
conformations of the US calculations according to the
description in the Materials and Methods section. The
sampling is guaranteed due to the overlap of histograms
(Figure S5). The free energy profile along the unbinding
pathway of the dissociation process was constructed utilizing
GROMACS tool “gmx wham”. The obtained potential of mean
force (PMF) of the US simulations is presented in Figure 7.
■
Figure 7. Dissociation free energy profile along the reaction
coordinate ξ was obtained from the PMF analysis using WHAM.
The error was earned through 100 rounds of the bootstrapping
estimation.71
MATERIALS AND METHODS
Molecular Dynamics Simulations. GROMACS 5.1.3 was
employed to mimic the solvated S4Aβ11−42 peptide, which was
extracted from the Aβ11−42 fibril structure with PDB ID:
2MXU.52 The peptides were represented using an Amber99SB-ildn force field, 75 referring to a previous
work,24,28,30 because the force field adopts the strongest
agreement with NMR and circular dichroism results.76 The
peptide was inserted into the dodecahedron periodic boundary
condition box with a size of ∼310 nm3 referring to previous
works.77,78 Water molecules were treated by a TIP3P model79
and four Na+ ions were used to keep neutralization of the
system. The soluble system was consisted of approximately 31
000 atoms. The simulations were performed by following three
steps including energy minimization, equilibrium simulation
(using short NVT and NPT simulations), and MD simulations.
The parameters of the MD simulations were chosen according
to the previous study.10 In particular, the Langevin dynamics
simulation was employed to mimic the solvate Aβ system. The
nonbond pair is updated every 5 ps with a cut-off of 0.9 nm.
The electrostatic interaction was represented using the particle
mesh Ewald with a cut-off of 0.9 nm. The van der Waals
interaction is effective when the pair is smaller than 0.9 nm.
During the simulation, all the bonds were constrained using
the LINCS method.80 The conformational change of the
S4Aβ11−42 peptide was chased every 10 ps.
US Calculation. Dissociation free energy of an edge chain
to the rest of S4Aβ11−42 is able to characterize through the US
simulations referring to a previous study.68 In particular, as
mentioned above, the MD-refined shape A was selected as the
model of the unbinding process analysis. Shape A was rotated
until the unbinding pathway along the reaction coordinate ξ as
shown in Figure 6. The Aβ peptide was then inserted into the
new solvated PBC box with the size of 6.14 × 6.40 × 10.32 nm
to provide appropriate space for the dissociating system. The
system thus consists of 4 Aβ11−42 monomers, 12 734 and 4 Na+
ions with 40118 atoms totally.
The solvated system was then energy minimization before
the steered-MD approach was employed to unbind the Aβ11−42
The PMF-curve morphology is in good agreement with
previous studies.67,70 The PMF curve energizes starting at the
zero value, then fall downs to the lowest amount, finally the
PMF value then increases to the equilibrium state when ξ
accomplishes ∼2 nm (Figure 7). The range is significantly
larger than that of the protein-ligand system (∼1.0 nm),67
which associates with the nonbonded cut-off. It happens
because the Aβ trimer structure was prolonged during SMD
simulations because the C-terminal is slower in motion than
the N-terminal. The PMF stable region indicates that the
nonbond between the trimer and the monomer is completely
terminated. The free-energy value ΔGUS was determined as the
variation between the smallest and largest values of the PMF
according to the explanation given in Figure 7. Here, the free
energy value is ΔGUS = −58.44 ± 1.26 kcal/mol, whereas the
error was detected through 100 rounds of the bootstrapping
estimation.71 The obtained binding free energy is approximately at the same level with the corresponding metric of the
U-shape Aβ17‑42 system, which is −50.50 kcal/mol.68 Moreover, it is noted that the calculated free energy ΔGUS is often
larger than the experimental amount.67,68,72 The difference is
caused by the exaggeration of simulating the interaction among
component molecules, including the peptide and water
molecules.73,74 The S-shape Aβ11−42 oligomer is approximately
stable like the U-shape Aβ17‑42 system. In other words, the
observed probability of S-shape Aβ42 oligomers is seemingly
similar to the U-shape systems.
■
CONCLUSIONS
In summary, the S-shape 4Aβ11−42 peptide, deriving from a
photofibril structure, 2MXU,52 was mimicked over a long time
MD simulations. The tetramer changes over the first 4 μs of
MD simulations, and then achieves the equilibrium state
during the last 6 μs of MD simulations. The structural change
study indicated that the S4Aβ11−42 oligomer is quite flexible
involving a high dynamics N-terminal. This may lead to
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trimer out of the rest of the monomer according to the
description given in Figure 6. In particular, the Aβ monomer,
which was noted as chain D, was restrained using a weak
harmonic force during the SMD simulations. The center of
mass of the Aβ trimer, including chain A, B, and C, an
externally harmonic force was applied with a spring constant
cantilever of k = 1000 kJ/mol/nm2 and pulling speed of v =
0.005 nm/ps. The direction of the pulling force is mentioned
in Figure 6. Several snapshots recording the unbinding process
between the Aβ trimer and monomer were archived along the
reaction coordinate ξ. Thirty-one windows were selected to
perform the US simulations to evaluate the dissociation free
energy profile using the PMF calculations through WHAM
analysis.69 The spacing between two neighboring windows is
∼0.1 nm. A short NPT simulation length 100 ps with the
positional-restrained condition was performed to relax the
solvated system. The relaxed systems were imposed to the US
calculation over 10 ns. There are entirely 3.1 μs of MD
simulations employed for US calculations.
Structural Analysis. The DSSP protocol46 was used to
compute the S4Aβ11−42 secondary structure. The IMPACT
package81 was employed to estimate the collisional cross
section (CCS). The rmsd, radius of gyration (Rg), and solvent
accessible surface area (SASA) were detected by GROMACS
tools. An intermolecular side-chain pair between various
residues is available when the spacing between the nonhydrogen atoms of different residues is smaller than 0.45 nm.
The FEL was generated using collective variables: backbone
rmsd and intermolecular side-chain contact.
■
ASSOCIATED CONTENT
S Supporting Information
*
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acsomega.9b00992.
rmsd and RMSF of the tetramer system, the FEL with
supposition of the self-assembly pathway, and the
histograms of the US simulations (PDF)
■
AUTHOR INFORMATION
Corresponding Author
*E-mail: ngosontung@tdtu.edu.vn
ORCID
Nguyen Thanh Tung: 0000-0003-0232-7261
Philippe Derreumaux: 0000-0001-9110-5585
Van V. Vu: 0000-0003-0009-6703
Pham Cam Nam: 0000-0002-7257-544X
Son Tung Ngo: 0000-0003-1034-1768
Author Contributions
All authors designed the studies, collected, analyzed data, and
wrote the manuscript.
Notes
The authors declare no competing financial interest.
■
■
ACKNOWLEDGMENTS
This work was supported by the Institute of Materials Science,
Vietnam Academy of Science and Technology to N.T.T.
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