Molecular dynamics studies of a β-sheet blocking peptide with the full-length amyloid beta peptide of Alzheimer’s disease

The region encompassing residues 13–23 of the amyloid beta peptide (Aβ(13–23)) of Alzheimer’s disease is the self-recognition site that initiates toxic oligomerization and fibrillization. A number of pseudopeptides have been designed to bind to Aβ(13–23) and been computationally shown to do so with high affinity. More interactions are available in full-length Aβ than are available in the shorter peptide. We describe herein a study by molecular dynamics (MD) of nine distinct complexes formed by one such pseudopeptide, SGA1, with full-length beta amyloid, Aβ(1–42). The relative stabilities of the Aβ–SGA1 complexes were estimated by a combination of MD and ab initio methods. The most stable complex, designated AB1, was found to be one in which SGA1 is bound to the self-recognition site of Aβ(1–42) in an antiparallel β-sheet fashion. Another complex, designated AB3, also involved SGA1 binding to the self-recognition region of Aβ(1–42), albeit with lower affinity. In both AB1 and AB3, SGA1 formed antiparallel β-sheets but to opposite edges of Aβ. A complex, AB4, with similar stability to AB3, was found with a parallel β-sheet in the self-recognition site. A fourth complex, AB7, also with similar stability, formed a parallel β-sheet in the hydrophobic central region of Aβ. In all cases, complexation of SGA1 induced extensive β-sheet structure in Aβ(1–42).

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Molecular dynamics study of the monomers and dimers of N-AcAβ(13–23)NH2: on the effect of pH on the aggregation of the amyloid beta peptide of Alzheimer’s disease

Canadian Journal of Chemistry ◽

10.1139/cjc-2015-0036 ◽

2016 ◽

Vol 94 (4) ◽

pp. 273-281 ◽

Cited By ~ 8

Author(s):

Stanley K.A. Opare ◽

Anahit Petoyan ◽

Banafsheh Mehrazma ◽

Arvi Rauk

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Molecular Dynamics ◽

Amyloid Beta ◽

Salt Bridge ◽

Umbrella Sampling ◽

Amyloid Beta Peptide ◽

Effect Of Ph ◽

Reverse Process ◽

Beta Peptide

The region encompassed by residues 13–23 of the amyloid beta peptide (Aβ(13–23)) of Alzheimer’s disease is the self-recognition site that initiates toxic oligomerization and fibrillization and also is the site of interaction of Aβ with many other proteins. We describe herein a study by molecular dynamics of N-AcAβ(13–23)NH2 (N-CH3C(O)HHQKLVFFAEDNH2) as a model of full-length Aβ(1–40) or Aβ(1–42) and of its dimers. The effect of pH at or below physiological (pH 7.4) is assessed by protonation of one or more of the His residues. The major conformation of the monomer of the systems is a flexible folded structure. Protonation of one or both His residues does not change the conformation in any significant way. The dimers of protonated and unprotonated systems exist almost exclusively as stable antiparallel β-sheets anchored at both ends by intermolecular salt bridges between Lys16 of one chain and the C-terminal residues Glu22 and Asp23 of the other. We also employ the technique of “umbrella sampling” whereby relative binding affinities of the complexes could be determined. In the case of unsymmetrically protonated species, each complex begins dissociation by releasing the weaker salt bridge, breaking interstrand hydrogen bonds, and losing the β-sheet character. The stronger salt bridge is the last to release and presumably is the first to form in the reverse process of aggregation. Umbrella sampling yields the free energy profiles of the dissociation as a function of the separation of the centres of mass. For each system, the dissociation profile has only a shallow maximum. By implication, the reverse process of assembly has almost no barrier. This is an example of entropy–enthalpy compensation that arises naturally during the molecular dynamics – umbrella sampling simulation.

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Alzheimer’s disease: unraveling APOE4 binding to amyloid-beta peptide and lipids with molecular dynamics and quantum mechanics

Journal of Biomolecular Structure and Dynamics ◽

10.1080/07391102.2020.1784287 ◽

2020 ◽

pp. 1-7

Author(s):

Jean-Numa Gillet

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Molecular Dynamics ◽

Quantum Mechanics ◽

Amyloid Beta ◽

Amyloid Beta Peptide ◽

Beta Peptide

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Curcumin Inhibits the Primary Nucleation of Amyloid-Beta Peptide: A Molecular Dynamics Study

Biomolecules ◽

10.3390/biom10091323 ◽

2020 ◽

Vol 10 (9) ◽

pp. 1323

Author(s):

Irini Doytchinova ◽

Mariyana Atanasova ◽

Evdokiya Salamanova ◽

Stefan Ivanov ◽

Ivan Dimitrov

Keyword(s):

Molecular Dynamics ◽

Hydrogen Bonds ◽

Amyloid Beta ◽

Amyloid Plaques ◽

Amyloid Beta Peptide ◽

Aβ Peptides ◽

Amyloid Peptides ◽

Primary Nucleation ◽

Beta Peptide ◽

Good Agreement

The amyloid plaques are a key hallmark of neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease. Amyloidogenesis is a complex long-lasting multiphase process starting with the formation of nuclei of amyloid peptides: a process assigned as a primary nucleation. Curcumin (CU) is a well-known inhibitor of the aggregation of amyloid-beta (Aβ) peptides. Even more, CU is able to disintegrate preformed Aβ firbils and amyloid plaques. Here, we simulate by molecular dynamics the primary nucleation process of 12 Aβ peptides and investigate the effects of CU on the process. We found that CU molecules intercalate among the Aβ chains and bind tightly to them by hydrogen bonds, hydrophobic, π–π, and cation–π interactions. In the presence of CU, the Aβ peptides form a primary nucleus of a bigger size. The peptide chains in the nucleus become less flexible and more disordered, and the number of non-native contacts and hydrogen bonds between them decreases. For comparison, the effects of the weaker Aβ inhibitor ferulic acid (FA) on the primary nucleation are also examined. Our study is in good agreement with the observation that taken regularly, CU is able to prevent or at least delay the onset of neurodegenerative disorders.

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