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Assessing the Stability of Alzheimer’s Amyloid Protofibrils Using Molecular Dynamics
Justin A. Lemkul, David R. Bevan. The Journal of Physical Chemistry B, 2010-01-07
Topic: Disease mechanisms in lab and animal studies
Amyloid fibrils represent a stable form of many misfolded proteins associated with numerous diseases. Among these are Parkinson's disease (alpha-synuclein), Type II diabetes (islet amyloid polypeptide), and Alzheimer's disease (amyloid beta-peptide, Abeta). The appearance of Abeta fibrils in neural tissue is a hallmark of Alzheimer's disease, and many studies have been conducted to determine and analyze the structure of these protein aggregates. The principal toxic species in Alzheimer's disease are believed to be soluble, oligomeric aggregates of Abeta, but numerous studies have found that the insoluble fibrillated form of the peptide also contributes to neurotoxicity. Thus, to design therapeutic agents to combat the progression of Alzheimer's disease, it is worthwhile to understand the thermodynamics of destabilizing these aggregates and the features that contribute to their stability. In this work, we present a systematic study of several factors that influence the stability of Abeta(42) fibrils following in silico mutation. We have employed standard molecular dynamics, as well as center-of-mass pulling and umbrella sampling, to study the thermodynamics of peptide dissociation from the core of a model protofibril at physiological temperature. Results indicate that a finite level of hydration around the Asp23-Lys28 salt bridge is crucial to protofibril stability, while mutation of Phe19 to glycine has no effect on the binding free energy of the terminal peptide. Packing between Ile32 and the aliphatic portion of the Lys28 side chain serves to regulate the level of hydration in the core of the protofibril and thus rigidify the Asp23-Lys28 salt bridge. These observations are important for designing compounds that target Abeta aggregates; interrupting these native interactions may destabilize these assemblies and ameliorate their toxicity.
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APA 7th
Lemkul, J. A., & Bevan, D. R. (2010). Assessing the Stability of Alzheimer’s Amyloid Protofibrils Using Molecular Dynamics. The Journal of Physical Chemistry B. https://doi.org/10.1021/jp9110794
Vancouver
Lemkul JA, Bevan DR. Assessing the Stability of Alzheimer’s Amyloid Protofibrils Using Molecular Dynamics. The Journal of Physical Chemistry B. 2010. doi:10.1021/jp9110794. PMID: 20055378.
BibTeX
@article{lemkul2010-20055378,
author = {Lemkul, Justin A. and Bevan, David R.},
title = {{Assessing the Stability of Alzheimer’s Amyloid Protofibrils Using Molecular Dynamics}},
journal = {The Journal of Physical Chemistry B},
year = {2010},
doi = {10.1021/jp9110794},
pmid = {20055378},
url = {https://doi.org/10.1021/jp9110794}
}
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Key findings
- Amyloid fibrils represent a stable form of many misfolded proteins associated with numerous diseases.
- Results indicate that a finite level of hydration around the Asp23-Lys28 salt bridge is crucial to protofibril stability, while mutation of Phe19 to glycine has no effect on the binding free energy of the terminal peptide.
Study details
- Evidence strengthLow
How this study scored 36/100
Published in a peer-reviewed journal. Scored zero for study design, sample size, effect reported, studied in people and randomised / blinded because the record does not state it. We have no data on journal's citation record, times cited, citations per year, impact for its field and year, cited by studies here, still being cited, senior author's track record, institution's track record and multi-centre collaboration, so those were left out: it earned 21 of the 58 points we could judge it on, which is 36 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (The Journal of Physical Chemistry B) |
| Journal's citation record | — / 4 | No journal record from OpenAlex — left out of this score |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 1 / 5 | Rated “low” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 1 / 5 | 2010 — within 20 year(s) of the newest study here |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Not stated whether this was studied in people — scores zero (not stated in the record — scored 0) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | — / 7 | No citation count (not found in OpenAlex) — left out of this score |
| Citations per year | — / 5 | No citation count or no year — left out of this score |
| Impact for its field and year | — / 6 | No field-weighted citation impact (OpenAlex has none yet) — left out of this score |
| Cited by studies here | — / 6 | Not yet checked against this library's citation graph — left out of this score |
| Still being cited | — / 4 | No yearly citation counts — left out of this score |
| Senior author's track record | — / 4 | Senior author's record not available — left out of this score |
| Institution's track record | — / 3 | No institution listed in OpenAlex — left out of this score |
| Multi-centre collaboration | — / 3 | Institutions not listed — left out of this score |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 20055378) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Points | 21 / 58 | Scored on 11 of 20 parts. We have no data for the rest, so they are left out: 21 of the 58 points we could judge it on is 36 out of 100. |
| Total | 36 / 100 | — |
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