Effects of Familial Alzheimer's Disease Mutations on the Folding Free Energy and Dipole-Dipole Interactions of the Amyloid β-Peptide.
Effects of Familial Alzheimer's Disease Mutations on the Folding Free Energy and Dipole-Dipole Interactions of the Amyloid β-Peptide.
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DOI：
10.1021/acs.jpcb.2c03520
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发表时间：
2022-10-06
影响因子：
3.3
通讯作者：
Lemkul, Justin A.
中科院分区：
文献类型：
--
作者：
Davidson, Darcy S.;Kraus, Joshua A.;Montgomery, Julia M.;Lemkul, Justin A.
家族性阿尔茨海默病（FAD）淀粉样β肽（Aβ）突变已知导致早发性和更具侵袭性的阿尔茨海默病。FAD突变如“爱荷华州”（D23 N）、“北极”（E22 G）、“意大利”（E22 K）和“荷兰”（E22 Q）已显示相对于野生型（WT）加速Aβ聚集。这些突变促进聚集增加的机制尚不清楚，但每个突变都会导致肽的净电荷发生变化。以前的研究使用非极化力场来研究Aβ，为这种蛋白质如何展开提供了一些见解。然而，不可极化的力场具有固定的电荷，这些电荷缺乏响应局部电场变化而重新分布的能力。在这里，我们对WT和FAD突变的全长Aβ42进行了极化分子动力学（MD）模拟，并通过伞形采样计算了Aβ15-27片段的折叠自由能。通过研究全长Aβ42和含有突变的片段以及中心疏水簇（残基17-21），我们能够系统地研究这些FAD突变如何影响二级和三级结构以及折叠热力学。静电相互作用，包括永久性和诱导偶极子之间的相互作用，影响侧链性质，盐桥，和溶剂的相互作用。FAD突变导致在中央疏水簇和疏水C-末端区域的电子结构和溶剂可及性的变化。使用伞形取样，我们发现WT和E22突变体的折叠是由构象驱动的，而D23 N突变体是由熵驱动的，这是由不同的解折叠途径和肽键偶极响应引起的。总之，片段的无偏、全长和伞形取样模拟揭示了FAD突变扰动疏水区域中的附近残基和其他残基以潜在地改变溶解度。这些结果突出了电子极化率在淀粉样蛋白错误折叠中的作用，以及构象变化时出现的异质微环境的作用。
Familial Alzheimer’s disease (FAD) mutations of the amyloid β-peptide (Aβ) are known to lead to early onset and more aggressive Alzheimer’s disease. FAD mutations such as “Iowa” (D23N), “Arctic” (E22G), “Italian” (E22K), and “Dutch” (E22Q) have been shown to accelerate Aβ aggregation relative to the wild-type (WT). The mechanism by which these mutations facilitate increased aggregation is unknown, but each mutation results in a change in net charge of the peptide. Previous studies have used nonpolarizable force fields to study Aβ, providing some insight into how this protein unfolds. However, nonpolarizable force fields have fixed charges that lack the ability to redistribute in response to changes in local electric fields. Here, we performed polarizable molecular dynamics (MD) simulations on the full-length Aβ42 of WT and FAD mutations and calculated folding free energies of the Aβ15–27 fragment via umbrella sampling. By studying both the full-length Aβ42 and a fragment containing mutations and the central hydrophobic cluster (residues 17–21), we were able to systematically study how these FAD mutations impact secondary and tertiary structure and the thermodynamics of folding. Electrostatic interactions, including those between permanent and induced dipoles, affected sidechain properties, salt bridges, and solvent interactions. The FAD mutations resulted in shifts in the electronic structure and solvent accessibility at the central hydrophobic cluster and the hydrophobic C-terminal region. Using umbrella sampling, we found that the folding of the WT and E22 mutants are enthalpically driven, whereas the D23N mutant is entropically driven, arising from a different unfolding pathway and peptide-bond dipole response. Together, the unbiased, full-length and umbrella sampling simulations of fragments reveal that the FAD mutations perturb nearby residues and others in hydrophobic regions to potentially alter solubility. These results highlight the role electronic polarizability plays in amyloid misfolding and the role of heterogeneous microenvironments that arise as conformational change takes place.
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影响因子：
4.4
作者：
Horn, HW;Swope, WC;Head-Gordon, T
通讯作者：
Head-Gordon, T
影响因子：
2.9
作者：
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通讯作者：
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DOI：
10.1093/protein/11.9.761
发表时间：
1998-09-01
期刊：
PROTEIN ENGINEERING
影响因子：
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作者：
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通讯作者：
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影响因子：
5.6
作者：
Davidson, Darcy S.;Brown, Anne M.;Lemkul, Justin A.
通讯作者：
Lemkul, Justin A.
影响因子：
4.4
作者：
FELLER, SE;ZHANG, YH;BROOKS, BR
通讯作者：
BROOKS, BR