A Dominant Factor for Structural Classification of Protein Crystals

Qi, Fei; Fudo, Satoshi; Neya, Saburo; Hoshino, Tyuji

doi:10.1021/acs.jcim.5b00052

Cited by 11 publications

(20 citation statements)

References 28 publications

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“…The Cterminal domain of Aβ 42 , residue [29][30][31][32][33][34][35][36][37][38][39][40][41][42], is composed of nonpolar residues and thus has strong hydrophobicity. The domain contains 4 Glys, which enhance the structural flexibility and increase the tendency for formation of a coil or a bend in the secondary structure.…”

Section: Roles Of Several Residues In An Aβ Complexmentioning

confidence: 99%

Simulation Study on Complex Conformations of Aβ<sub>42</sub> Peptides on a GM1 Ganglioside-Containing Lipid Membrane

2018

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Aggregation and complex formation of amyloid beta (Aβ) peptides on a neuronal cell membrane is a hallmark of neuro-disturbance diseases. In this work, we performed molecular dynamics (MD) simulations to investigate the initial stage of interactions of multiple Aβ 42 peptides on a GM1 ganglioside-containing membrane that mimics a micro-domain on the neuronal cell surface. Conformational changes of Aβs due to adhesion on the membrane and subsequent molecular interactions among the Aβs were monitored. It was suggested from results of the two 1.0 µs simulation trials that stable complexes of Aβ peptides were not rapidly generated but that a steady binding of two Aβs was gradually formed. Observation of two Aβs that will be a complex with steady binding revealed that one Aβ was bound to the membrane surface, while the other was attached to the first one without strong contact with the membrane. The motion of the first one was restricted and its conformational change was limited, with the basic side-chains of Arg5 and Lys28 working as anchors to hold the Aβ helix region on the membrane. In contrast, the second one had high flexibility and showed diversity in its conformation. The second Aβ can search for an energetically favorable binding position on the first one. A parallel β-sheet structure was formed between the C-terminal sides of the two Aβs. Ala30 was critically important to lead the stable β-sheet conformation at the C-terminal hydrophobic domains of Aβs. In the N-terminal sides, helix structures were kept in both Aβs.Key words amyloid beta peptide; molecular dynamics simulation; membrane surface; molecular interaction; conformational change; complex structure Aggregation of amyloid beta (Aβ)-peptides is closely linked to several neurodegeneration diseases including Alzheimer's disease (AD).1-3) Aβ is a small peptide consisting of typically 39-43 amino acid residues and it is a normal product of cellular metabolism from amyloid precursor protein (APP) due to the successive proteolytic action by β-and γ-secretases. 4,5) Aggregation and resultant transformation of Aβ peptides into insoluble misfolding proteins is a pathological hallmark of neurodegeneration diseases in the brain.4) The most commonly observed forms of toxic Aβs are comprised of 40 and/or 42 residues. Both of them show an affinity to a lipid membrane, but Aβ 42 (a.a. 1-42) is more likely to form amyloid fibrils. 6)This strong tendency of Aβ 42 to aggregate is related to two additional hydrophobic amino acids at its C-terminal end. 7)According to an in vivo study, 8) soluble Aβ oligomers were sequestered from brain interstitial fluid onto brain membranes more rapidly than non-toxic monomers and they were strongly bound to GM1-ganglioside on the cellular membranes. GM1 is likely to form a cluster on a membrane containing sphingomyelin (SM) and cholesterol (Chol). A GM1 cluster has a hydrophobic surface and a negatively charged area due to the condensation of glycans. Many in vitro studies have shown an acceleration of Aβ aggregation on lipid micro-d...

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Section: Roles Of Several Residues In An Aβ Complexmentioning

confidence: 99%

Simulation Study on Complex Conformations of Aβ<sub>42</sub> Peptides on a GM1 Ganglioside-Containing Lipid Membrane

2018

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“…The snapshot structures were depicted by PyMOL. 24) For a better understanding of simulation structures, the positions of some Aβ molecules were transferred along x, y, or z-direction by the side length of the periodic boundary box.…”

Section: Analysis Of Simulation Resultsmentioning

confidence: 99%

Computational Study on the Assembly of Amyloid β-Peptides in the Hydrophobic Environment

Fudo

Hoshino

2019

CHEMICAL & PHARMACEUTICAL BULLETIN

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Fibrillated aggregation of amyloid β (Aβ) peptides is a potential factor causing toxic amyloid deposition in neurodegenerative diseases. A toxic fibril formation of Aβ is known to be enhanced on the ganglioside-rich lipid membrane containing some amounts of cholesterol and sphingomyelin. This ganglioside-rich membrane is supposed to provide a hydrophobic environment that promotes the formation of Aβ fibrils. Molecular dynamics simulations were carried out to investigate the structure of Aβ complex in the hydrophobic solution composed of dioxane and water molecules. The Aβ conformation was contrasted to that in the aqueous condition by executing multiple computational trials with the calculation models containing one, four, or six Aβ peptides. The conformation was also compared between the calculations with the 42-mer (Aβ 42) and 40-mer (Aβ 40) peptides. The simulations for Aβ 42 demonstrated that Aβ peptides had a tendency to stretch out in the hydrophobic environment. In contrast, Aβ peptides were closely packed in the aqueous solution, and the motions of Aβ peptides were suppressed significantly. The N-terminal polar domains of Aβ peptides tended to be positioned at the inside of the Aβ complex in the hydrophobic environment, which supported the C-terminal domains in expanding outward for inter-molecular interaction. Since Aβ peptides were not tightly packed in the hydrophobic environment, the total surface area of the Aβ complex in the hydrophobic solution was larger than that in the aqueous one. The simulation for Aβ 40 peptides also showed a difference between the hydrophobic and aqueous solutions. The difference was compatible with the results of Aβ 42 in the structure of the Aβ complex, while the C-terminal outward expansion was not so distinct as Aβ 42 peptides.

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“…25) Atom charges of the compound were determined by the quantum chemical calculation in a similar manner to the previous works. [26][27][28] Compound 1 stayed at the catalytic site all through the simulations both for poses A and B. The binding structures were, however, changed from those of the starting models.…”

Section: Evaluation Of Inhibitory Activitymentioning

confidence: 97%

Identification of the Inhibitory Compounds for Metallo-β-lactamases and Structural Analysis of the Binding Modes

Kamo

Kuroda

Kondo

et al. 2021

CHEMICAL & PHARMACEUTICAL BULLETIN

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A Dominant Factor for Structural Classification of Protein Crystals

Cited by 11 publications

References 28 publications

Simulation Study on Complex Conformations of Aβ<sub>42</sub> Peptides on a GM1 Ganglioside-Containing Lipid Membrane

Simulation Study on Complex Conformations of Aβ<sub>42</sub> Peptides on a GM1 Ganglioside-Containing Lipid Membrane

Computational Study on the Assembly of Amyloid β-Peptides in the Hydrophobic Environment

Identification of the Inhibitory Compounds for Metallo-β-lactamases and Structural Analysis of the Binding Modes

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