Dynamic properties of pH-dependent structural organization of the amyloidogenic β-protein (1-40)

Figures & data

Figure 1 Dynamics behavior of the radii of gyration (Rg) of Aβ40 during MD simulations performed for (A and B) initial structures at both considered pHs. Notes: Plots of the radii of gyration calculated (in Angstrom) for backbone atoms (Cα, C, N) of Aβ40 at pH 8 and pH 3 are shown in the upper and lower parts of the figure, correspondingly. Colored curves correspond to the A (magenta) and B (blue) initial structures (see Methods).

Figure 2 Percentage (%) of involvement of the amino acid residues within the Aβ40 sequence in forming the secondary structural elements (structural propensity) during the last 10 ns of MD simulations at pH 8: (A and B) present secondary structure sets determined by the analyses of the RSA₈ and RSB₈ structural sets, correspondingly. Notes: The secondary structure elements were depicted by different colors: α-helix (green), 3₁₀-helix (blue), β-turn (yellow) and random coil (red).

Figure 3 The trace of the C_α-atoms of the average Ω-shaped structure formed by the Ala21-Gly29 segment in the stable state at pH 8.

Figure 4 A typical three-dimensional structure formed by the Glu22-Gly29 segment in the stable state at pH 8. Notes: Observed H-bonds between polar groups are shown by dash-lines. CD, CG, OG and NZ note the heavy atoms of the donor-acceptor groups of the interacting residues.

Figure 5 Schematic presentation of the major structural states of the Glu11-Val36 segment of the Aβ40 core domain considered at pH 8 and pH 3. The rectangular blocks along the sequence designate the flexible and fluctuating helix-like structural modes: Glu11-Phe20 (Helix 1′) at pH 8; Glu11-Val24 (Helix 1) at pH 3, and Ala30-Val36 (Helix 2) at both pHs. The Ala21-Gly29 residues at pH 8 form the Ω-shaped structure (comprised of about 84% of the MD generated structures). The Gly25-Gly29 residues at both pHs form a bend-shaped structure.

Figure 6 Helical net layout of the Glu11-Gly37 segment. Notes: The sequence is presented by the net diagram typical for two α-helices, formed by the Glu11-Val24 (Helix 1) and Ala30-Val36 (Helix 2) segments. The residues forming the continuous hydrophobic clusters are marked by dark circles. The residues forming the bend structures (Gly25-Gly29) are marked by the hexagons. The numbers present the positions of the corresponding amino acid residues in the Aβ40 sequence.

Table 1 The structural propensities (occupation percentage) of amino acid residues within Glu11-Val39 segment to be involved in the formation of secondary structure elements revealed from the RSA₈ and RSA₃ structural sets at the last 10 ns of the MD simulations

	RSA8				RSA3
	G	H	T	C	G	H	T	C
Glu11	31	18	30	21	30	28	29	13
Val12	32	25	39	4	33	31	27	8
His13	29	24	43	3	27	29	26	17
His14	18	25	48	8	24	23	30	22
Gln15	13	17	52	17	23	27	26	24
Lys16	23	14	41	22	28	24	30	17
Leu17	38	20	34	8	29	31	30	10
Val18	38	20	31	10	20	34	37	8
Phe19	34	18	25	23	27	38	28	6
Phe20	17	13	38	32	28	36	31	5
Ala21	9	4	37	49	29	32	32	6
Glu22	3	1	36	60	20	26	37	17
Asp23	1	0	0	98	13	18	36	32
Val24	1	0	1	98	9	8	43	40
Gly25	1	0	1	98	7	7	26	59
Ser26	3	1	8	87	21	9	36	34
Asn27	4	2	16	78	21	11	34	34
Lys28	5	3	17	74	22	13	34	31
Gly29	19	10	27	43	12	13	30	45
Ala30	27	15	31	26	32	15	32	21
Ile31	33	20	33	13	34	14	39	13
Ile32	31	27	32	8	33	19	33	14
Gly33	27	25	26	21	22	20	39	17
Leu34	32	22	30	15	29	24	37	10
Met35	28	18	39	15	26	22	43	9
Val36	16	10	51	23	17	17	49	16
Gly37	3	4	38	54	3	10	41	44
Gly38	0	1	14	85	1	1	23	75
Val39	0	0	5	95	0	0	8	91

Notes: G, 3₁₀-helix; H, α-helix; T, β-turn and C, random coil.

Table 2 The structural propensities (occupation percentage) of amino acid residues within Glu11-Val39 segment to be involved in the formation of secondary structure elements revealed from the RSB8 and RSB3 structural sets at the last 10 ns of the MD simulations RSA₈ RSA₃

	G	H	T	C	G	H	T	C
Glu11	43	11	36	10	19	31	13	37
Val12	45	22	28	4	23	24	27	27
His13	48	24	22	5	24	20	32	23
His14	33	27	34	6	21	22	34	23
Gln15	30	21	22	28	32	21	29	18
Lys16	41	14	32	12	34	21	37	9
Leu17	43	26	25	6	36	31	27	6
Val18	42	31	24	3	28	37	26	8
Phe19	37	31	28	3	38	40	20	2
Phe20	25	27	43	5	27	41	29	3
Ala21	14	13	58	15	28	35	28	9
Glu22	2	4	64	31	20	30	38	11
Asp23	0	0	0	100	16	26	44	14
Val24	0	0	1	99	9	17	53	20
Gly25	0	0	1	99	6	16	38	40
Ser26	0	0	7	92	22	12	46	18
Asn27	0	0	10	89	23	10	55	10
Lys28	1	1	12	86	20	10	44	24
Gly29	15	3	18	63	13	7	32	46
Ala30	49	8	27	16	31	12	30	26
Ile31	52	16	25	7	34	13	34	19
Ile32	49	22	22	6	31	23	28	17
Gly33	25	24	41	9	22	23	31	23
Leu34	28	25	38	8	32	23	33	11
Met35	26	18	47	9	30	22	38	9
Val36	19	12	52	17	26	14	45	14
Gly37	3	6	40	51	9	9	43	36
Gly38	1	0	18	81	2	2	37	59
Val39	0	0	9	91	1	1	12	86

Notes: G, 3₁₀-helix; H, α-helix; T, β-turn and C, random coil.

Table 3 Percentage (%) of helical structures adopted by five tetrapeptide segments of Aβ40 at pH 8 and pH 3

	pH 8			pH 3
Segment	Type of helix	RMSD^a	% (%A + %B)^b	RMSD^a	% (%A + %B)^b
E11-H14
	α	0.3	95.7 (48.3 + 47.4)	0.7	87.8 (45.1 + 42.7)
	310	0.7	4.2 (1.7 + 2.5)	0.4	10.0 (4.0 + 6.0)
H14-L17
	α	0.3	74.8 (41.6 +33.2)	0.3	82.3 (39.7 + 42.6)
	310	0.9	20.2 (7.3 + 12.9)	1.1	14.8 (7.8 + 7.0)
L17-F20
	α	0.4	88.1 (43.2 + 44.9)	0.4	85.9 (43.8 + 42.1)
	310	0.6	9.1 (4.2 + 4.9)	1.3	13.6 (6.1 + 7.5)
A30-G33
	α	0.3	90.4 (43.7 + 46.7)	0.3	81.5 (43.1 + 38.4)
	310	0.7	7.7 (5.6 + 2.1)	0.6	15.6 (5.6 + 10.0)
G33-V36	α	0.3	91.8 (45.5 + 46.3)	0.3	91.1 (45.6 + 45.5)

Notes: ^a-Numbers show RMSD (in Angstrom) between the heavy atoms of the main chain of the considered tetrapeptides and the analogous atoms of helixes. ^b-% before parenthesis is overall percentage of structures that were assigned to the given cluster; %A and %B—percentage of structures within the given cluster that were generated during the MD simulations starting from the A and B initial structures, correspondingly.

Table 4 The percentage (%) of structures assigned to the most populated clusters formed by the Ala21-Gly29 segment and overall description of the structures formed by the Ala21-Val24 residues

pHs	Cluster's number	Ala21-Gly 29 %	Ala21-Val24 structure
pH 8	1	84	hook
	2	5	hook
	3	4	β-strand
	4	3	helix-like
pH 3	5	39	α-helix
	6	14	α-helix
	7	11	β-turn
	8	6	3/10-turn

Notes: The population percentage (%) of the clusters was determined using RMSD ≤ 1.6 Å as the criterion of structural similarity. For each cluster, structures formed by the Ala21-Val24 residues are described by their appearance and/or due to their RMSD closeness to the considered structures.

Table 5 Percentage of the cases (%), in which the hydrogen bonds (H-bonds) between the donor-acceptor groups of the residues within the Glu22-Gly29 segment are formed

Amino acid pairs	Heavy atoms of the donor-acceptor groups	H-bonds (%)
Glu22-Lys28	CD…NZ	51
Asp23-Val24	CG…NH	59
Asp23-Gly25		89
Asp23-Ser26		70
Asp23-Asn27		76
Asp23-Lys28		68
Asp23-Gly29		58
Asp23-Ser26	CG…OG	24

Note: %—the percentage of cases of forming the given hydrogen bonds when the Gl22-Gly29 segment is in the stable state.