Oligomeric structures and strand orientations of Aβ(16-22) and
its E22Q mutant revealed by all-atom simulations
Xuhua Li, Jiangtao Lei, and Guanghong Wei
State Key Laboratory of Surface Physics and Department of Physics, Fudan University, Shanghai 200433, China
Introduction
Alzheimer’s disease (AD) is associated with the pathological self-assembly of
amyloid-β (Aβ) peptides into β-sheet enriched fibrillar aggregates.[1] The amyloidβ(Aβ) polypeptide, varying from 39 to 43 amino acid residues in length, is produced
by the cleavage of the amyloid precursor protein through sequential cleavage by both
β- and γ-secretase. Aβ(16–22)(with amino acid sequence KLVFFAE) containing the
central hydrophobic core of Aβ (LVFFA), is one of the shortest peptides that form
amyloid fibrils morphologically similar to full-length Aβ fibrils at neutral pH[2]
Recent isotope-edited IR and solid-state NMR experiments reported that the minimal
nucleating core of the Dutch mutant of Aβ(16-22), E22Q, assembles initially as
antiparallel β-strands that later transition completely into fibrils with parallel βstrands, while Aβ(16-22) forms fibrils with antiparallel β-strands.[3] However, the
molecular mechanisms behind the different β-strand alignments in Aβ(16-22) and
Aβ(16-22)E22Q remain illusive. In this work, we performed extensive all-atom replica
exchange molecular dynamics simulations on the octamers of Aβ(16-22) and E22Q
mutant.
Our simulation results show that the mutant has a higher propensity to form parallel β
strands than the wild-type and more dimer and hexamer in the mutant system (Figure 4).
(a)
(b)
Figure 4 Analysis of strand orientation and β-sheet size distribution in Aβ(16-22)
(black) and Aβ(16-22)E22Q mutant (red). (a) The probability density function
(PDF) of the angle between two β-stands. (b) The probability of β-sheet size.
The E22Q mutation significantly alters the free energy landscape.
Materials
The sequence of Aβ(16-22) and Aβ(16-22)E22Q
peptides is KLVFFAE and KLVFFAQ, respectively.
Their initial state is shown in Figure 1.
(a)
Model
(b)
Figure1. (a) Aβ(16-22) and (b) Aβ(16-22)E22Q
All-atom protein model – Amber99SB-ILDN
(a)
(b)
Figure 5. Free energy surface (in kcal/mol) for Aβ(16-22) (a) and Aβ(1622)E22Q (b) as a function of radius gyration (Rg) and the total number intraand intermolecular H-bonds (H-bond number).
Methods
Use Newtonian mechanics to calculate the net force and acceleration experienced by each atom
(F = ma).
d 2 ri
Fi mi 2
dt
( R)
The E22Q mutation significantly enhances the inter-peptide interactions for residues in
the C-terminal of the peptide. Figure 6 shows the contact maps of side-chain—side-chain
and main-chain—main-chain for the two systems.
Replica exchange molecular dynamics (REMD) simulation method (Figure 2).
REMD simulations were performed on octamers with 48 replicas with temperature ranging
from 309-410 K for the Aβ(16-22) wild-type and Aβ(16-22)E22Q mutant, respectively.
Results
The secondary structure probability
between wild-type and mutant is
similar, with a slight difference in βsheet and β-bridge.
Figure 1. Calculated secondary
structure probabilities for Aβ(16-22)
and E22Q mutant.
Compared with wild-type, the coil probability of
mutant is enhanced for residues L, V, F, and has a high
probability β-sheet for residue A which is in the Cterminal of the peptide. In addition mutant has a
higher propensity to sample β-bridge conformation.
(a)
(b)
(c)
(d)
Figure 2. Dominant secondary structure probability as a
function of each amino acid on both system. The coil (a);
the β-sheet (b); and the β-bridge(c) along the amino acid
sequence in Aβ(16-22) (black bar) and Aβ(16-22)E22Q
systems (red bar).
The various conformations here show a good convergence of REMD simulations and the E22Q
mutant displays more parallel β-strands than wild-type.
Figure 6. Intermolecular main-chain—main-chain (a) (b) and side-chain—
side-chain (c) (d) contact maps of Aβ(16-22) and Aβ(16-22)E22Q systems
respectively.
Conclusions
(a) Cluster_1 (11.7%) (b) Cluster_2 (9.8%)
(c) Cluster_3 (8.0%) (d) Cluster_4 (6.5%)
(g) Cluster_1 (12.4%) (h) Cluster_2 (5.8%) (i) Cluster_3 (5.4%)
(j) Cluster_4 (5.1%)
(e) Cluster_5 (6.3%) (f) Cluster_6 (4.1%)
(k) Cluster_5 (4.6%) (l) Cluster_6 (4.3%)
Figure 3. Representative conformations of the first six most-populated clusters of Aβ(16-22) (a)-(f) and
Aβ(16-22)E22Q (g)-(l)systems. The corresponding population of each cluster is given in parentheses.
The two system are presented by secondary structure method of newcartoon in VMD.
We have investigated the Aβ(16-22) wild-type and Aβ(16-22)E22Q mutant by
performing two 350-ns REMD simulations. Our simulations show that the Aβ(1622)E22Q has a higher propensity to form parallel β strands than Aβ(16-22).
Furthermore we find that the E22Q mutation significantly enhances the interpeptide interactions for residues in the C-terminal of the peptide, which is
favorable for the formation of parallel β strands. This study provides an
explanation for the different β strand orientations in their final assemblies
at the atomic level.
References
[1] Sun Y, Qian Z, Wei G. Physical Chemistry Chemical Physics, 2016, 18(18): 12582-12591.
[2] Balbach J J, Ishii Y, Antzutkin O N, et al. Biochemistry, 2000, 39(45): 13748-13759.
[3] Liang C, Ni R, Smith J E, et al. Journal of the American Chemical Society, 2014, 136(43): 15146-15149.