Molecular dynamic simulation study on co-aggregation between amyloid-β and Medin

PAN Wenyan; CHENG Chuanyong; NIU Jingjing; YUAN Bing; YANG Kai; DONG Xuewei

doi:10.7498/aps.74.20250616

Abstract
The aggregation of Medin is closely related to the arterial wall degeneration and cerebrovascular dysfunction. In patients with vascular dementia or Alzheimer’s disease, the concentration of medin in cerebral arterioles increases, and Medin is co-localized with vascular amyloid-β (Aβ) deposits. Previous study demonstrates that Medin interacts directly with Aβ, forming heterologous fibrils with Aβ and promoting Aβ aggregation. However, the basic mechanism of the co-aggregation between Medin and Aβ remains largely elusive. Here, we explore the interactions and conformational ensembles of Aβ₄₂/Medin trimers in different peptide environments (self-aggregation vs. co-aggregation) by performing all-atom replica exchange molecular dynamic simulation on Aβ₄₂/Medin homotrimers and Aβ₄₂-Medin heterotrimer with an accumulated simulation time of 72 μs. Our results reveal that Aβ₄₂ exhibits higher affinity with Medin, and Aβ₄₂ and Medin have similar molecular recognition sites in self-aggregation and co-aggregation. The N-terminus of Aβ₄₂ and the C-terminus of Medin play critical roles in Aβ₄₂-Medin cross-talk. More importantly, co-aggregation significantly changes the interaction strength, binding patterns and structural characteristics of Aβ₄₂ and Medin. Intermolecular interactions of Aβ₄₂ trimers are relatively weak among three trimers, and the binding sites are concentrated between N- and N-termini, between N- and C-termini, and between C- and C-termini of Aβ₄₂. In contrast, intermolecular interactions of Medin trimers are the strongest, and the binding sites are widely and uniformly distributed in Medin peptides. Intermolecular interactions of Aβ₄₂ in Aβ₄₂-Medin heterotrimer decrease compared with those of Aβ₄₂ trimers, only the binding of the hydrophobic core regions (¹⁶KLVFFA²¹) is retained and other regions of Aβ₄₂ gain increase flexibility. Two-dimensional(2D) free energy landscapes reveal distinct conformational diversities between the homo- and heterotrimers, with the order of diversity being Medin/Aβ42-Medin trimers > Aβ42 trimers. The R_g of Aβ₄₂ trimers is smaller than those of the other two trimers, implying that Aβ₄₂ trimers possess a more compact structure, whereas Medin/Aβ₄₂-Medin trimers exhibit a relatively loose conformation. The Aβ₄₂ trimers possess the highest β content whereas Medin trimers exhibit the lowest β probability. It is found that Aβ₄₂-Medin co-aggregation induces Medin to form more β-structures with longer lengths and fewer helices, while promoting Aβ₄₂ to form more helices and fewer β-structures. High β-propensity regions of Medin in heterotrimers shift towards the C-terminus of Medin, suggesting that Medin utilizes its C-terminal β region as a core motif to drive its co-aggregation with Aβ₄₂. These results elucidate the detailed influences of co-aggregation on the interactions and conformations of Aβ₄₂ and Medin. This work provides key insights into the molecular mechanism of Aβ₄₂-Medin co-aggregation and the pathological mechanisms of cross-linking between related diseases.

Keywords:
peptide co-aggregation /

amyloid-β /

Medin /

molecular dynamic simulations
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图 1 Aβ₄₂/Medin同源三聚体与Aβ₄₂-Medin异源三聚体的相互作用分析　(a), (b)三个体系中多肽的(a)接触数与(b)氢键数的概率密度分布(probability density function, PDF); (c), (d) Aβ₄₂与Aβ₄₂-Medin三聚体体系中, Aβ₄₂-Aβ₄₂、Aβ₄₂-Medin之间的(c)接触数与(d)氢键数的PDF; (e)—(h)多肽分子间的残基-残基接触作用数图, 即(e)Aβ₄₂三聚体中Aβ₄₂-Aβ₄₂的残基-残基接触数图、(f) Aβ₄₂-Medin三聚体中Aβ₄₂-Aβ₄₂的残基-残基接触数图、(g) Medin三聚体中Medin-Medin的残基-残基接触数图、(h) Aβ₄₂-Medin三聚体中Aβ₄₂-Medin的残基-残基接触数图; (i)—(k)展示Aβ₄₂与Medin结合区域的代表性结构快照. 多肽以cartoon方式呈现. Aβ₄₂与Medin结合区域以蓝色和橘色突出显示, 并将区域两端对应的氨基酸标记在结构上

Figure 1. Analysis of interactions in Aβ₄₂/Medin homotrimers and Aβ₄₂-Medin heterotrimer: (a), (b) Probability density function (PDF) of (a) contact number and (b) hydrogen-bond (H-bond) number of peptides in three systems; (c), (d) PDF of (c) contact number and (d) H-bond number between Aβ₄₂ and Aβ₄₂ as well as between Aβ₄₂ and Medin in A-A^trimer and A-M^trimer systems; (e)–(h) 2D residue-residue contact maps of intermolecular interactions for (e) Aβ₄₂-Aβ₄₂ in A-A^trimer, (f) Aβ₄₂-Aβ₄₂ in A-M^trimer, (g) Medin-Medin in M-M^trimer and (h) Aβ₄₂-Medin in A-M^trimer; (i)–(k) representative snapshots illustrate the binding regions between Aβ₄₂ and Medin in A-M^trimer system.

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图 2 Aβ₄₂与Medin在同源与异源三聚体体系中的构象特征分析　(a)以链间接触数和回转半径为反应坐标的二维构象FELs: A-A^trimer体系(左)、M-M^trimer体系(中)、A-M^trimer体系(右); (b)—(d)聚类分析中概率最高的六个聚类构象簇(C1—C6)的中心结构及每个聚类对应的概率(标记在对应中心结构下方): (b) Aβ₄₂三聚体、(c) Medin三聚体以及(d) Aβ₄₂-Medin三聚体. 这些聚类中心结构的位置标记在二维自由能图景(a)中. 多肽以cartoon方式呈现, 每条多肽链N端残基的Cα原子以小球标记. Aβ₄₂和Medin分别用橙色系和蓝色系颜色显示

Figure 2. Analysis of conformational characteristics of Aβ₄₂/Medin homotrimers and Aβ₄₂-Medin heterotrimer: (a) FELs as a function of intermolecular contact number and trimeric R_g in A-A^trimer (left), M-M^trimer (middle) and A-M^trimer (right) systems; (b)–(d) representative conformations for the six most-populated clusters (C1–C6) along with their corresponding populations (marked below the corresponding representative conformations) of (b) Aβ₄₂ trimer, (c) Medin trimer and (d) Aβ₄₂-Medin trimer. The locations of those representative conformations are labeled on the FEL plots. Aβ₄₂ and Medin are shown in cartoon, with the N-terminal Cα atom of each chain represented by a sphere. Aβ₄₂ and Medin peptides are colored in blue and orange, respectively.

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图 3 Aβ₄₂与Medin在同源与异源三聚体体系中的二级结构分析　(a)三个体系中的各种二级结构的概率统计; (b) Aβ₄₂与Medin在不同体系中形成helix结构的概率: A-A^trimer和A-M^trimer体系中的Aβ₄₂ (浅蓝vs.深蓝)以及M-M^trimer和A-M^trimer体系中的Medin (浅橙色vs.深橙色), 其中异源聚集体体系用*号表示; (c) Aβ₄₂与Medin在不同体系中形成β结构的概率; (d) β结构以链间和链内方式进行排列的概率; (e)三个体系的三聚体中β-sheet长度的概率分布; (f) A-A^trimer和A-M^trimer (*) 体系中Aβ₄₂的β-sheet长度的概率分布; (g) M-M^trimer和A-M^trimer (*) 体系中Medin的β-sheet长度的概率分布; (h)三个体系的三聚体中β-sheet尺寸的概率分布

Figure 3. Analysis of secondary structures of Aβ₄₂/Medin homotrimers and Aβ₄₂-Medin heterotrimer: (a) Each secondary structure probability of Aβ₄₂ homotrimer, Medin homotrimer and Aβ₄₂-Medin heterotrimer; (b) helix probability of Aβ₄₂ and Medin in different systems: Aβ₄₂ in A-A^trimer system (light blue) vs. Aβ₄₂ in A-M^trimer system (*, blue) and Medin in M-M^trimer system (light orange) vs. Medin in A-M^trimer system (*, orange); (c) β probability of Aβ₄₂ and Medin in different systems; (d) probability of β arrangement with interchain and intrachain manners; (e) probability of β-sheet length in three systems; (f) probability of β-sheet length of Aβ₄₂ in A-A^trimer and A-M^trimer systems; (g) probability of β-sheet length of Medin in M-M^trimer and A-M^trimer systems; (h) probability of β-sheet size in three systems.

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图 4 β结构概率和β结构形成区域的分析　(a), (c) A-A^trimer和A-M^trimer体系中Aβ₄₂的每个氨基酸形成β结构的概率; (b), (d) M-M^trimer和A-M^trimer体系中Medin的每个氨基酸形成β结构的概率. 富含β-sheet结构的代表性Aβ₄₂, Medin和Aβ₄₂-Medin三聚体构象展示在对应的残基-β结构概率图中. 多肽采用cartoon表示形式, Aβ₄₂与Medin中的β结构区域以蓝色和橙色突出显示

Figure 4. β-sheet probability and β-sheet formation regions of Aβ₄₂ and Medin in homotrimer and heterotrimer. Residue-based β probability distribution of Aβ₄₂ and Medin peptides respectively in (a) Aβ₄₂ homotrimer/(b) Medin homotrimer and (c), (d) Aβ₄₂-Medin heterotrimer. Representative β-sheet-rich conformations of Aβ₄₂, Medin and Aβ₄₂-Medin trimers are illustrated as insets in (a)–(d). Aβ₄₂ and Medin peptides are shown in cartoon with the β-sheet-rich regions highlighted in blue and orange, respectively.

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图 B1 高温MD模拟中Aβ₄₂单体的构象特征分析. 温度为500 K的高温MD模拟中,　(a) Aβ₄₂单体的回转半径R_g随时间的演化; (b)选做三聚体REMD模拟初始构象的Aβ₄₂单体的代表结构及其对应的时间点与R_g (Aβ₄₂以cartoon方式呈现并显示为蓝色, N端残基Cα原子以小球标记); (c) Aβ₄₂单体的五种二级结构(coil, β, bend, turn和helix)概率随时间的演化

Figure B1. Analysis of structural properties of Aβ₄₂ monomers in high temperature MD simulation: (a) Time evolution of monomeric R_g of Aβ₄₂; (b) representative conformations of Aβ₄₂ monomers selected as initial structures for peptide trimers in REMD, along with their corresponding time and R_g (Aβ₄₂ is shown in cartoon and colored in blue, with the N-terminal Cα atom represented by a sphere); (c) time evolution of secondary structure probabilities of Aβ₄₂ monomers.

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图 B2 高温MD模拟中Medin单体的构象特征分析. 温度为500 K的高温MD模拟中,　(a) Medin单体的回转半径Rg随时间的演化; (b)选做三聚体REMD模拟初始构象的Medin单体的代表结构及其对应的时间点与R_g (Medin以cartoon方式呈现并显示为橙色, N端残基Cα原子以小球标记); (c) Medin单体的五种二级结构(coil, β, bend, turn和helix)概率随时间的演化

Figure B2. Analysis of structural properties of Medin monomers in high temperature MD simulation. (a) Time evolution of monomeric R_g of Medin; (b) representative conformations of Medin monomers selected as initial structures for peptide trimers in REMD, along with their corresponding time and R_g (Medin is shown in cartoon and colored in orange, with the N-terminal Cα atom represented by a sphere); (c) time evolution of secondary structure probabilities of Medin monomers.

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图 B3 (a) A-A^trimer, (b) M-M^trimer和(c)A-M^trimer体系的12个初始状态. 多肽以cartoon方式呈现, 每条多肽链N端残基的Cα原子以小球标记. Aβ₄₂和Medin分别用橙色系和蓝色系颜色显示

Figure B3. 12 initial states of peptide trimers in (a) A-Atrimer, (b) M-Mtrimer and (c) A-Mtrimer systems. Aβ42 and Medin are shown in cartoon, with the N-terminal Cα atom of each chain represented by a sphere. Aβ42 and Medin peptides are colored in blue and orange, respectively.

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图 B4 A-A^trimer体系收敛性检测　(a) 310 K的副本编号随时间的演化; (b)—(d)体系的氢键数、R_g和接触数的PDF; (e)每种二级结构的概率; (f)—(k)不同二级结构在每个氨基酸上的平均概率. 选用的时间间隔为300—400 ns和400—500 ns

Figure B4. Simulation convergence assessments for A-A^trimer system: (a) The time evolution of one representative temperature (310 K) in replica space; (b)–(d) PDF of H-bond number, R_g and contact number; (e) the average probability of each dominant secondary structures (including coil, β, bend, turn and helix); (f)–(k) the secondary structure propensity of each residue. The convergence is checked using the data generated within the time intervals of 300–400 ns and 400–500 ns.

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图 B5 M-M^trimer体系收敛性检测　(a) 310 K的副本编号随时间的演化; (b)—(d)体系的氢键数、R_g和接触数的PDF; (e)每种二级结构的概率; (f)—(k) 不同二级结构在每个氨基酸上的平均概率. 选用的时间间隔为300—400 ns和400—500 ns

Figure B5. Simulation convergence assessments for M-M^trimer system: (a) The time evolution of one representative temperature (310 K) in replica space; (b)–(d) PDF of H-bond number, R_g and contact number; (e) the average probability of each dominant secondary structures (including coil, β, bend, turn and helix); (f)–(k) the secondary structure propensity of each residue. The convergence is checked using the data generated within the time intervals of 300–400 ns and 400–500 ns.

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图 B6 A-M^trimer体系收敛性检测　(a) 310 K的副本编号随时间的演化; (b)—(d)体系的氢键数、R_g和接触数的PDF; (e)每种二级结构的概率; (f)—(k)不同二级结构在每个氨基酸上的平均概率. 选用的时间间隔为300—400 ns和400—500 ns

Figure B6. Simulation convergence assessments for A-M^trimer system: (a) The time evolution of one representative temperature (310 K) in replica space; (b)–(d) PDF of H-bond number, R_g and contact number; (e) the average probability of each dominant secondary structures (including coil, β, bend, turn and helix); (f)–(k) the secondary structure propensity of each residue. The convergence is checked using the data generated within the time intervals of 300–400 ns and 400–500 ns.

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图 B7 Aβ₄₂-Aβ₄₂, Medin-Medin和Aβ₄₂-Medin结合的代表性“热点”残基之间相互作用的结构快照. Aβ₄₂-Aβ₄₂结合位点:　(a) A-A^trimer体系中的F19-K28, Y10-V12以及(b) A-M^trimer体系中的F20-F20, L17-F20. Medin-Medin结合位点: (c) M-M^trimer体系中的F8-W11, W21-F48. Aβ₄₂-Medin结合位点: (d) A-M^trimer体系中的F19-F43, I31-W11.

Figure B7. Representative snapshots illustrate the hot residue-residue interactions in peptide trimers. Aβ₄₂-Aβ₄₂ binding sites: (a) F19-K28/Y10-V12 in A-A^trimer system and (b) F20-F20 and L17-F20 in A-M^trimer system. Medin-Medin binding sites: (c) F8-W11/W21-F48 in M-M^trimer system. Aβ₄₂-Medin binding sites: (d) F19-F43/I31-W11 in A-M^trimer system.

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图 B8 Aβ₄₂与Medin相互作用区域的分析　(a), (c), (e) Medin在Aβ₄₂上的结合位点: Medin与Aβ₄₂中每一个残基之间的(a)总接触数、(c)氢键数与(e)疏水接触数. (b), (d), (f) Aβ₄₂在Medin上的结合位点: Aβ₄₂与Medin中每一个残基之间的(b)总接触数、(d)氢键数与(f)疏水接触数

Figure B8. Analysis of interaction regions between Aβ₄₂ and Medin. (a), (c), (e) Medin binding sites on Aβ₄₂: (a) total contact number, (c) H-bond number and (e) hydrophobic contact number between Medin and each residue of Aβ₄₂. (b), (d), (f) Aβ₄₂ binding sites on Medin: (b) total contact number, (d) H-bond number and (f) hydrophobic contact number between Aβ₄₂ and each residue of Medin.

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图 B9 Aβ₄₂/Medin同源三聚体与Aβ₄₂-Medin异源三聚体体系中多肽的链内残基-残基接触数图　(a) A-A^trimer体系、(b) A-M^trimer体系中的Aβ₄₂链内残基对接触数图及(c)二者的差值图; (d) M-M^trimer体系、(e) A-M^trimer体系中的Medin链内残基对接触数图及(f)二者的差值图

Figure B9. Intramolecular residue-residue contact maps of Aβ₄₂/Medin homotrimers and Aβ₄₂-Medin heterotrimer. Intramolecular residue-residue contact maps of Aβ₄₂ peptides in (a) A-A^trimer and (b) A-M^trimer systems as well as (c) their difference. Intramolecular residue-residue contact maps of Medin peptides in (d) A-A^trimer and (e) A-M^trimer systems as well as (f) their difference.

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图 B10 (a), (c), (e) A-A^trimer和A-M^trimer体系中Aβ₄₂的每个氨基酸形成helix结构的概率及二者之间的差值; (b), (d), (f) M-M^trimer和A-M^trimer体系中Medin的每个氨基酸形成helix结构的概率及二者之间的差值

Figure B10. Residue-based helix probability distribution of Aβ₄₂ and Medin peptides respectively in (a), (b) homo-A-A^trimer/M-M^trimer and (c), (d) hetero-A-M^trimer systems as well as (e), (f) their differences.

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表 A1 高温MD模拟中选择作为Aβ₄₂单体构象的时间点

Table A1. Time points for selected conformations of Aβ₄₂ monomer from the high temperature MD simulation.

	Time/ns
Aβ₄₂	0	0.04	0.24	0.30	0.31	0.35
	0.36	0.39	0.42	2.98	3.03	3.05
	3.07	3.08	3.13	3.42	3.55	3.57
	3.73	3.94	3.96	3.99	4.52	4.53
	4.77	4.79	4.83	4.87	5.08	5.22
	5.71	5.97	6.29	6.31	6.49	9.67

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表 A2 高温MD模拟中选择作为Medin单体构象的时间点

Table A2. Time points for selected conformations of Medin monomer from the high temperature MD simulation.

	Time/ns
Medin	0	0.01	0.02	0.03	0.04	0.05
	0.06	0.07	0.08	0.09	0.10	0.11
	0.12	0.13	0.14	0.15	8.67	9.16
	22.45	23.94	29.81	35.05	35.09	38.50
	45.26	53.75	59.83	62.65	63.04	63.08
	63.11	65.68	65.75	65.87	65.93	67.03

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表 A3 A-A^trimer体系中48个副本的温度列表.

Table A3. Temperature list for 48 replicas in A-A^trimer system.

	Temperature/K
A-A^trimer	308.18	310.00	311.83	313.66	315.49	317.35	319.21	321.07
	322.95	324.84	326.73	328.63	330.54	332.47	334.39	336.33
	338.28	340.23	342.20	344.17	346.15	348.14	350.14	352.15
	354.18	356.20	358.24	360.29	362.35	364.42	366.49	368.57
	370.67	372.77	374.89	377.01	379.15	381.29	383.45	385.61
	387.78	389.96	392.16	394.36	396.58	398.80	401.04	403.29

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表 A4 M-M^trimer体系中48个副本的温度列表.

Table A4. Temperature list for 48 replicas in M-M^trimer system.

	Temperature/K
M-M^trimer	308.18	310.00	311.82	313.66	315.50	317.35	319.20	321.07
	322.88	324.77	326.66	328.56	330.47	332.39	334.32	336.25
	338.19	340.14	342.10	344.07	346.05	348.04	350.04	352.05
	354.06	356.09	358.12	360.17	362.22	364.28	366.36	368.44
	370.53	372.62	374.73	376.86	378.99	381.13	383.27	385.43
	387.60	389.79	391.98	394.18	396.39	398.61	400.84	403.08

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表 A5 A-M^trimer体系中48个副本的温度列表.

Table A5. Temperature list for 48 replicas in A-M^trimer system.

	Temperature/K
A-M^trimer	308.18	310.00	311.83	313.66	315.50	317.35	319.23	321.09
	322.96	324.85	326.74	328.65	330.56	332.48	334.40	336.31
	338.26	340.21	342.17	344.15	346.13	348.12	351.12	353.14
	355.16	357.19	359.23	361.28	363.34	365.41	367.49	369.58
	371.68	373.79	375.91	378.03	380.17	382.32	384.48	386.64
	388.82	390.98	393.17	395.38	397.60	399.83	402.07	404.32

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