Amyloid Fibril Disruption by Ultrasonic Cavitation: Nonequilibrium Molecular Dynamics Simulations

Okumura, Hisashi; Itoh, Satoru

doi:10.1021/ja502749f

Cited by 88 publications

(92 citation statements)

References 35 publications

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“…)404142 was used to perform the MD simulations. The AMBER parm99SB force field43 was used for the TRP channel and the general AMBER force field was used for HC39.…”

Section: Methodsmentioning

confidence: 99%

Structural basis of TRPA1 inhibition by HC-030031 utilizing species-specific differences

Gupta

Saito

Mori

et al. 2016

Sci Rep

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Pain is a harmful sensation that arises from noxious stimuli. Transient receptor potential ankyrin 1 (TRPA1) is one target for studying pain mechanisms. TRPA1 is activated by various stimuli such as noxious cold, pungent natural products and environmental irritants. Since TRPA1 is an attractive target for pain therapy, a few TRPA1 antagonists have been developed and some function as analgesic agents. The responses of TRPA1 to agonists and antagonists vary among species and these species differences have been utilized to identify the structural basis of activation and inhibition mechanisms. The TRPA1 antagonist HC-030031 (HC) failed to inhibit frog TRPA1 (fTRPA1) and zebrafish TRPA1 activity induced by cinnamaldehyde (CA), but did inhibit human TRPA1 (hTRPA1) in a heterologous expression system. Chimeric studies between fTRPA1 and hTRPA1, as well as analyses using point mutants, revealed that a single amino acid residue (N855 in hTRPA1) significantly contributes to the inhibitory action of HC. Moreover, the N855 residue and the C-terminus region exhibited synergistic effects on the inhibition by HC. Molecular dynamics simulation suggested that HC stably binds to hTRPA1-N855. These findings provide novel insights into the structure-function relationship of TRPA1 and could lead to the development of more effective analgesics targeted to TRPA1.

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“…)404142 was used to perform the MD simulations. The AMBER parm99SB force field43 was used for the TRP channel and the general AMBER force field was used for HC39.…”

Section: Methodsmentioning

confidence: 99%

Structural basis of TRPA1 inhibition by HC-030031 utilizing species-specific differences

Gupta

Saito

Mori

et al. 2016

Sci Rep

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“…Despite great progress achieved in the field, the exact role of Aβ is still not well understood. 6 Numerous therapeutic approaches (such as use of Aβ-degrading enzymes, 7 the ultrasound technique, 8,9 mid-infrared free-electron laser technology, 10 etc.) that target the production, toxicity and removal of Aβ have been developed during the past decade.…”

Section: Introductionmentioning

confidence: 99%

Elucidating Important Sites and the Mechanism for Amyloid Fibril Formation by Coarse-Grained Molecular Dynamics

Rojas

Maisuradze

Kachlishvili

et al. 2016

ACS Chem. Neurosci.

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Fibrils formed by the β-amyloid (Aβ) peptide play a central role in the development of Alzheimer’s disease. In this study, the principles governing their growth and stability are investigated by analyzing canonical and replica-exchange molecular dynamics trajectories of Aβ(9–40) fibrils. In particular, an unstructured monomer was allowed to interact freely with an Aβ fibril template. Trajectories were generated with the coarse-grained united-residue force field, and one- and two-dimensional free-energy landscapes (FELs) along the backbone virtual-bond angle θ and backbone virtual-bond-dihedral angle γ of each residue and principal components, respectively, were analyzed. Also, thermal unbinding (unfolding) of an Aβ peptide from the fibril template was investigated. These analyses enable us to illustrate the entire process of Aβ fibril elongation and to elucidate the key residues involved in it. Several different pathways were identified during the search for the fibril conformation by the monomer, which finally follows a dock-lock mechanism with two distinct locking stages. However, it was found that the correct binding, with native hydrogen bonds, of the free monomer to the fibril template at both stages is crucial for fibril elongation. In other words, if the monomer is incorrectly bound (with nonnative hydrogen bonds) to the fibril template during the first “docking” stage, it can remain attached to it for a long time before it dissociates and either attempts a different binding or allows another monomer to bind. This finding is consistent with an experimentally-observed “stop-and-go” mechanism of fibril growth.

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“…Several MD simulation studies have revealed the aggregation131415161718192021222324 and disaggregation252627 of A β amyloid fibrils, and a few MD studies have reported easy deformation of the A β molecules at the two fibril ends under high temperature (398 K) conditions2829. However, the structural and fluctuational differences between the odd and even ends have not been investigated.…”

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confidence: 99%

Structural and fluctuational difference between two ends of Aβ amyloid fibril: MD simulations predict only one end has open conformations

Okumura

Itoh

2016

Sci Rep

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Aβ amyloid fibrils, which are related to Alzheimer’s disease, have a cross-β structure consisting of two β-sheets: β1 and β2. The Aβ peptides are thought to be serially arranged in the same molecular conformation along the fibril axis. However, to understand the amyloid extension mechanism, we must understand the amyloid fibril structure and fluctuation at the fibril end, which has not been revealed to date. Here, we reveal these features by all-atom molecular dynamics (MD) simulations of Aβ42 and Aβ40 fibrils in explicit water. The structure and fluctuation were observed to differ between the two ends. At the even end, the Aβ peptide always took a closed form wherein β1 and β2 were closely spaced. The Aβ peptide fluctuated more at the odd end and took an open form wherein the two β-sheets were well separated. The differences are attributed to the stronger β-sheet formation by the β1 exposed at the even end than the β2 exposed at the odd end. Along with the small fluctuations at the even end, these results explain why the fibril extends from one end only, as observed in experiments. Our MD results agree well with recent observations by high-speed atomic force microscopy.

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Amyloid Fibril Disruption by Ultrasonic Cavitation: Nonequilibrium Molecular Dynamics Simulations

Cited by 88 publications

References 35 publications

Structural basis of TRPA1 inhibition by HC-030031 utilizing species-specific differences

Structural basis of TRPA1 inhibition by HC-030031 utilizing species-specific differences

Elucidating Important Sites and the Mechanism for Amyloid Fibril Formation by Coarse-Grained Molecular Dynamics

Structural and fluctuational difference between two ends of Aβ amyloid fibril: MD simulations predict only one end has open conformations

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