Amyloid-β Peptide Structure in Aqueous Solution
Varies with Fragment Size
Olivia Wise-Scira1, Liang Xu1, Taizo Kitahara1, George Perry2, Orkid Coskuner1,2*,
1
The University of Texas at San Antonio, Department of Chemistry, One UTSA Circle, San Antonio,
Texas 78249 and 2The University of Texas at San Antonio, Neurosciences Institute, One UTSA Circle,
San Antonio, Texas 78249
Email: orkid.coskuner@utsa.edu
(a)
(b)
(c)
Figure S1. The calculated intra-molecular interactions of the (a) Aβ16, (b) Aβ28 and (c) Aβ42 peptides.
The color scale corresponds to the probability (P) of the distance between any two heavy atoms of the
two residues being ≤ 4.5 Å.
1
Peptide
Aβ16
Aβ28
Aβ42
Secondary Structure
A
B - Basin I
α-helix
7.7%
7.6%
310-helix
7.6%
8.0%
β-sheet
1.6%
1.9%
Turn
21.0%
21.6%
Coil
62.0%
60.9%
Secondary Structure
A
α-helix
B
Basin IA
Basin IB
16.9%
12.1%
23.4%
310-helix
9.9%
7.4%
10.5%
β-sheet
1.3%
2.8%
0.7%
Turn
24.2%
25.9%
23.1%
Coil
47.4%
51.7%
41.9%
Secondary Structure
A
α-helix
B
Basin IA
Basin IB
15.0%
10.0%
21.5%
310-helix
10.7%
9.1%
9.5%
β-sheet
3.0%
6.2%
1.1%
Turn
30.0%
41.6%
28.2%
Coil
40.9%
32.4%
39.6%
Table S1. The average secondary structure abundances of Aβ16, Aβ28 and Aβ42 using (A) all
converged structures and (B) structures located in basin I and basins IA and IB for each peptide (Figure
4). The abundance of π-helix is not displayed.
Figure S2. Probability distribution of Rg for the Aβ16 (black), Aβ28 (red) and Aβ42 (blue) peptides.
The probability is based on the number of structures using a bin of 0.1 Å.
2
Before calculating the PMF surfaces of each peptide, we first calculated the probability distribution
of Rg (Fig. S2). All three peptides adopt conformations that vary in the degree of compactness but this
variation is larger for Aβ28. The calculated average Rg values are 8.8±1.1 Å, 11.2±1.5 Å and 12.1±1.6
Å for Aβ16, Aβ28 and Aβ42, respectively. The Rg value for Aβ42 is in agreement with previously
reported Rg values including those by Baumketner et al., Lee and Ham, and Ball et al.1-3
In order to verify the convergence in our PMF calculations, the PMF values were calculated based
on Rg and RE-E values using different simulation times (Figure S3). These results show similar trends
and further indicate that the PMF is converged.
(a)
(b)
Figure S3. PMF surfaces based on RE-E and Rg values of the Aβ42 peptide using the converged
structures from the first (a) 90 ns and (b) 95 ns of our simulations time.
(a)
(b)
Figure S4. The simulated (a) α-helix and (b) β-sheet abundances and their associated Gibbs free
energies (G) using the harmonic approximation of the Aβ42 peptide structures. No clear trend is
obtained between the secondary structure abundances and G.
3
The α-helix and β-sheet abundances of the structures of Aβ42 do not show dependence with
increasing or decreasing conformational G values (Figure S3). The α-helix and β-sheet abundances of
the structures of Aβ16 do not show a clear trend with the magnitude of the corresponding G values
neither.
Basin I
7.6
8.0
1.9
21.6
60.9
Basin II
7.9
8.0
1.3
20.6
62.2
Basin III
5.3
8.2
1.5
17.4
67.5
α-helix (%)
310-helix (%)
β-sheet (%)
Turn (%)
Coil (%)
Table S2a. The secondary structure probabilities of the Aβ16 structures located in basin I, basin II,
basin III (see Figure 4). The abundance of π-helix is not displayed.
Basin IA
12.1
7.4
2.8
25.9
51.7
Basin IIA
11.0
10.0
2.0
27.1
49.6
Basin IIIA
12.0
11.5
1.3
26.9
49.3
Basin IB
23.4
10.5
0.7
23.1
41.9
Basin IIB
20.1
11.0
0.7
23.0
45.0
Basin IIIB
15.0
10.6
0.4
20.9
52.9
α-helix (%)
310-helix (%)
β-sheet (%)
Turn (%)
Coil (%)
Table S2b. The secondary structure probabilities of the Aβ28 structures located in basin IA, basin IIA,
basin IIIA, basin IB, basin IIB, basin IIIB of the PMF surface (see Figure 4b). The abundance of π-helix
is not displayed.
Basin IA
10.0
9.1
6.2
32.4
41.6
Basin IIA
14.5
9.5
3.6
29.5
42.5
Basin IIIA
15.3
11.0
2.4
28.1
42.7
Basin IB
21.5
9.5
1.1
28.2
39.6
Basin IIB
15.8
11.4
2.6
30.3
39.7
Basin IIIB
15.2
11.1
2.9
29.5
41.0
α-helix (%)
310-helix (%)
β-sheet (%)
Turn (%)
Coil (%)
Table S2c. The secondary structure probabilities of the Aβ42 structures located in basin IA, basin IIA,
basin IIIA, basin IB, basin IIB, basin IIIB (see Figure 4). The abundance of π-helix is not displayed.
4
(a)
(b)
Figure S5. The intra-molecular peptide interactions for the Aβ16 peptide structures located in (a) basin II
and basin III of the PMF surface (Figure 4). The color scale corresponds to the probability (P) of the
distance between the centers of mass of two residues being ≤ 9 Å. The interactions obtained for basin I are
presented in Figure 6a.
(a)
(b)
(c)
(d)
Figure S6. The intra-molecular peptide interactions for the Aβ28 structures located in (a) basin IIA, (b)
basin IIIA, (c) basin IIB and (d) basin IIIB on the PMF surface (Figure 4). The color scale corresponds
to the probability (P) of the distance between the centers of mass of two residues being ≤ 9 Å. The
interactions for basins IA and IB are shown in Figures 6b and 6c, respectively.
5
(a)
(b)
(c)
(d)
Figure S7. The intra-molecular peptide interactions for the Aβ42 structures located in (a) basin IIA, (b)
basin IIIA, (c) basin IIB and (d) basin IIIB on the PMF surface (Figure 4). The color scale corresponds
to the probability (P) of the distance between the centers of mass of two residues being ≤ 9 Å. The
interactions for basins IA and IB are shown in Figures 6d and 6e, respectively.
Donor
Acceptor
Arg5
Glu3
Arg5
Lys16 (-COO-)
Arg5
Glu11
Arg5
Asp1
Arg5
Asp7
Asp1 (-NH3+)
Glu3
Lys16
Glu11
Lys16
Asp7
Lys16
Glu3
Lys16
Asp1
R(C-N) ≤ 4 Å R(C-N) ≤ 5 Å R(C-N) ≤ 6 Å
(%)
(%)
(%)
100.0
48.3
36.1
26.6
3.2
2.4
2.2
1.1
0.9
0.6
100.0
58.0
51.3
34.2
4.7
3.2
3.8
1.6
1.5
1.1
100.0
86.3
76.8
51.8
7.7
3.6
4.5
1.8
1.9
1.2
Scheme S1. The formed salt bridges of Aβ16; R(C-N) is the distance between carboxylate C atom and
the side-chain or N-terminus N atom. Representative Aβ16 structures with salt bridges are depicted
along with table. The secondary structures by residue of Aβ16 are represented by the following colors:
α-helix (blue), 310-helix (gray), π-helix (purple), β-sheet (red), β-bridge (black), turn (yellow), coil
(white).
6
Donor
R(C-N) ≤ 4 Å R(C-N) ≤ 5 Å R(C-N) ≤ 6 Å
(%)
(%)
(%)
Acceptor
Glu3
Arg5
Asp1
Arg5
Glu11
Arg5
Arg5
Glu22
Glu11
Lys16
Lys16
Asp23
Arg5
Asp7
Arg5
Asp23
Arg5
Lys28 (-COO-)
Asp7
Lys16
Asp1
Lys16
Glu3
Lys16
Asp1 (-NH3+)
Glu3
Asp7
Lys28
100.0
52.6
41.9
25.3
6.8
6.4
5.1
4.9
2.2
2.1
1.6
1.3
0.8
0.8
100.0
60.9
59.8
33.9
11.9
8.7
6.8
5.9
2.7
3.1
3.1
2.3
1.2
1.4
100.0
92.0
90.7
49.9
14.2
9.2
11.5
8.8
4.0
3.6
3.3
2.7
1.7
1.5
Scheme S2. The formed salt bridges of Aβ28; R(C-N) is the distance between carboxylate C atom and
the side-chain or N-terminus N atom. Representative Aβ28 structures with salt bridges are depicted
along with table. The secondary structures by residue of Aβ28 are represented by the following colors:
α-helix (blue), 310-helix (gray), π-helix (purple), β-sheet (red), β-bridge (black), turn (yellow), coil
(white).
Donor
Acceptor
Glu3
Glu11
Arg5
Asp1
Arg5
Arg5
Lys16
Lys28
Glu11
Lys16
Asp7
Asp1
Arg5
Arg5
Ala42 (-COO-)
Arg5
Asp23
Glu22
Glu22
Ala42 (-COO-)
Lys16
Asp23
Lys16
Lys16
R(C-N) ≤ 4 Å R(C-N) ≤ 5 Å R(C-N) ≤ 6 Å
(%)
(%)
(%)
100.0
65.5
31.8
31.2
27.9
10.3
4.5
3.4
2.4
1.4
0.8
0.7
100.0
84.6
37.1
33.0
30.4
11.7
8.0
4.9
4.9
4.1
1.3
1.0
100.0
100.0
55.3
56.1
45.3
17.4
9.9
5.6
6.4
9.4
1.7
1.1
Scheme S3. The formed salt bridges of Aβ42; R(C-N) is the distance between carboxylate C atom and
the side-chain or N-terminus N atom. Representative Aβ42 structures with salt bridges are depicted
along with table. The secondary structures by residue of Aβ42 are represented by the following colors:
α-helix (blue), 310-helix (gray), π-helix (purple), β-sheet (red), β-bridge (black), turn (yellow), coil
(white).
Salt bridge formations in the Asp1-Lys16 region of Aβ16 and Aβ28 are similar (Schemes S1 and S2)
except for the more abundant Arg5-Asp1 and Lys16-Glu11 salt bridges in Aβ28. The Arg5 and Asp1 or
7
Glu11 salt bridges are more stable in Aβ42 than in Aβ16 (Schemes S1 and S3). In comparison to Aβ16
and Aβ28, the Aβ42 peptide structures do not form salt bridges between Arg5 and Asp7, the N-terminus
and Glu3, and Lys16 and Glu3 or Glu22. Furthermore, the Arg5-Glu11 and Arg5-Asp23 salt bridge
abundances increase by 20-30% for Aβ42 in comparison to Aβ28. Despite, the Asp1-Arg5 and Arg5Glu22 salt bridge abundances decrease by 20-30% for Aβ42 in comparison to the Aβ28 peptide
structures (Schemes S1-S3). These reported salt bridge formations are in partial agreement with the
results for the Ala21-Ala30 region reported by Yang and Teplow by REMD simulations using an
implicit water model.4
Donor
Acceptor
Basin I
(%)
Basin II
(%)
Basin III
(%)
Arg5
Arg5
Arg5
Arg5
Arg5
Asp1-NH3+
Lys16
Lys16
Lys16
Lys16
Glu3
Lys16-COOGlu11
Asp1
Asp7
Glu3
Glu11
Asp7
Glu3
Asp1
100.0
100.0
24.6
10.1
1.4
2.1
0.8
0.3
1.1
0.3
100.0
22.1
41.0
32.6
4.7
2.5
2.3
1.2
0.7
0.5
89.3
21.3
38.2
37.6
5.9
3.2
3.0
0.9
1.9
0.2
Table S3a. The salt bridges for the Aβ16 structures located in basin I, basin II and basin III for a R(CN) distance of ≤ 4 Å (see Figure 4).
8
Donor
Acceptor
Basin IA
(%)
Basin IIA
(%)
Basin IIIA
(%)
Arg5
Arg5
Arg5
Arg5
Lys16
Lys16
Arg5
Arg5
Arg5
Lys16
Lys16
Lys16
Asp1-NH3
Lys28
Glu3
Asp1
Glu11
Glu22
Glu11
Asp23
Asp7
Asp23
Lys28-COOAsp7
Asp1
Glu3
Glu3
Asp7
100.0
21.8
14.8
65.4
5.8
16.6
1.6
15.3
0.9
0.2
0.8
1.7
0.6
2.4
100.0
20.8
17.4
53.2
7.5
12.5
5.1
10.5
7.7
1.5
2.3
1.0
1.0
1.7
100.0
22.6
31.7
43.3
6.9
6.4
9.8
6.5
14.9
0.3
2.5
0.3
0.9
1.9
Donor
Acceptor
Basin IB
(%)
Basin IIB
(%)
Basin IIIB
(%)
Arg5
Arg5
Arg5
Arg5
Lys16
Lys16
Arg5
Arg5
Arg5
Lys16
Lys16
Lys16
Asp1-NH3+
Lys28
Glu3
Asp1
Glu11
Glu22
Glu11
Asp23
Asp7
Asp23
Lys28-COOAsp7
Asp1
Glu3
Glu3
Asp7
75.8
80.9
62.4
5.2
7.1
3.9
0.4
2.3
1.1
1.0
0.4
-
77.7
70.9
56.3
5.1
6.8
2.0
5.7
0.5
3.4
1.5
1.6
0.8
-
73.1
61.6
51.9
3.0
6.4
0.8
9.2
2.8
2.6
1.6
2.3
-
Table S3b. The formed salt bridges for the Aβ28 structures located in basin IA, basin IIA, basin IIIA,
basin IB, basin IIB and basin IIIB for a R(C-N) distance of ≤ 4 Å (see Figure 4).
9
Donor
Acceptor
Basin IA
(%)
Basin IIA
(%)
Basin IIIA
(%)
Arg5
Arg5
Arg5
Arg5
Arg5
Arg5
Lys16
Lys28
Lys16
Lys16
Lys16
Lys16
Glu3
Glu11
Ala42-COOAsp1
Asp23
Glu22
Glu22
Ala42-COOGlu11
Asp23
Asp7
Asp1
100.0
0.8
100.0
0.4
0.1
0.1
6.6
3.4
-
100.0
13.5
74.8
5.4
3.9
2.8
2.1
8.5
4.4
0.1
0.7
0.7
100.0
36.6
37.2
29.2
4.3
6.8
6.6
3.8
3.9
0.2
1.5
3.5
Donor
Acceptor
Basin IB
(%)
Basin IIB
(%)
Basin IIIB
(%)
Arg5
Arg5
Arg5
Arg5
Arg5
Arg5
Lys16
Lys28
Lys16
Lys16
Lys16
Lys16
Glu3
Glu11
Ala42-COOAsp1
Asp23
Glu22
Glu22
Ala42-COOGlu11
Asp23
Asp7
Asp1
100.0
100.0
1.3
31.5
3.2
2.3
0.4
1.1
3.7
87.6
97.1
41.9
48.3
16.7
4.5
1.2
1.5
2.3
1.0
0.5
87.6
65.0
58.4
15.5
8.2
11.3
2.5
1.6
1.0
0.8
0.2
Table S3c. The formed salt bridges for the Aβ42 structures located in basin IA, basin IIA, basin IIIA,
basin IB, basin IIB and basin IIIB of the PMF surface for a R(C-N) distance of ≤ 4 Å (see Figure 4).
The probabilities of the salt bridges between Arg5 and Asp1, Glu11, Glu22, or Asp23 in Aβ28 decrease
with increasing PMF values (Fig. 4 and Table S3). The salt bridges between Arg5 and Glu11 or Ala42
in Aβ42 show a decrease in probability with increasing PMF value (Fig. 4 and Table S3). The Asp1Lys16 region of Aβ28 shows salt bridge formation between Arg5 and Asp1 or Glu11 with a larger
stability in comparison to those in Aβ16 (Table S3). In parallel, these salt bridges have also a larger
stability in the Asp1-Lys16 region of Aβ42 than in the Aβ16 and Aβ28 (Table S3).
1.
M. T. Bowers, A. Baumketner, S. L. Bernstein, T. Wyttenbach, G. Bitan, D. B. Teplow and J. E.
Shea, Protein Sci 15 (3), 420-428 (2006).
2.
S. Ham and C. Lee, J Comput Chem 32 (2), 349-355 (2011).
3.
T. Head-Gordon, K. A. Ball, A. H. Phillips, P. S. Nerenberg, N. L. Fawzi and D. E. Wemmer,
Biochemistry-Us 50 (35), 7612-7628 (2011).
4.
D. B. Teplow and M. F. Yang, J Mol Biol 384 (2), 450-464 (2008).
10