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Three Popular Force Fields Predict Consensus Mechanism of Amyloid β Peptide Binding to the Dimyristoylgylcerophosphocholine Bilayer.
Journal of Chemical Information and Modeling ( IF 5.6 ) Pub Date : 2020-03-16 , DOI: 10.1021/acs.jcim.0c00096
Christopher Lockhart 1 , Amy K Smith 1 , Dmitri K Klimov 1
Affiliation  

Using all-atom explicit water replica-exchange molecular dynamics simulations, we examined the impact of three popular force fields (FF) on the equilibrium binding of Aβ10-40 peptide to the dimyristoylgylcerophosphocholine (DMPC) bilayer. The comparison included CHARMM22 protein FF with CHARMM36 lipid FF (C22), CHARMM36m protein FF with CHARMM36 lipid FF (C36), and Amber14SB protein FF with Lipid14 lipid FF (A14). Analysis of Aβ10-40 binding to the DMPC bilayer in three FFs revealed a consensus binding mechanism. Its main features include (i) a stable helical structure in the bound peptide, (ii) insertion of the C-terminus and, in part, the central hydrophobic cluster into the bilayer hydrophobic core, (iii) considerable thinning of the DMPC bilayer beneath the bound peptide coupled with significant drop in bilayer density, and (iv) a strong disordering in the DMPC fatty acid tails. Although the three FFs diverge on many details concerning Aβ and bilayer conformational ensembles, these discrepancies do not offset the features of the consensus binding mechanism. We compared our findings with other FF evaluations and proposed that an agreement between C22, C36, and A14 is a consequence of a strong ordering effect created by polar-apolar interface in the lipid bilayer. By comparing the consensus Aβ binding mechanism with experimental data, we surmise that the three tested FFs largely correctly capture the interactions of Aβ peptides with the DMPC lipid bilayer.

中文翻译:

三个流行的力场预测淀粉样蛋白β肽绑定到Dimyristoylgylcerophosphochocholine双层的共识机制。

使用全原子显式水复制-交换分子动力学模拟,我们检查了三个流行力场(FF)对Aβ10-40肽与二肉豆蔻酰gyrocrophophocholine(DMPC)双层平衡结合的影响。比较包括具有CHARMM36脂质FF(C22)的CHARMM22蛋白FF,具有CHARMM36脂质FF(C36)的CHARMM36m蛋白FF和具有Lipid14脂质FF(A14)的Amber14SB蛋白FF。分析三个FF中Aβ10-40与DMPC双层的结合,揭示了共有的结合机制。其主要特征包括(i)结合肽中稳定的螺旋结构,(ii)C末端插入,以及部分中央疏水簇进入双层疏水核中,(iii)下方的DMPC双层显着变薄结合的肽加上双层密度的显着下降,(iv)DMPC脂肪酸尾巴中的强烈紊乱。尽管三个FF在有关Aβ和双层构象集成的许多细节上存在分歧,但这些差异并未抵消共有结合机制的特征。我们将我们的发现与其他FF评估进行了比较,并提出C22,C36和A14之间的协议是脂质双层中极性-非极性界面产生的有序排列效果的结果。通过将共有的Aβ结合机制与实验数据进行比较,我们推测三个测试的FF在很大程度上正确地捕获了Aβ肽与DMPC脂质双层的相互作用。这些差异不会抵消共识绑定机制的特征。我们将我们的发现与其他FF评估进行了比较,并提出C22,C36和A14之间的协议是脂质双层中极性-非极性界面产生的有序排列效果的结果。通过将共有的Aβ结合机制与实验数据进行比较,我们推测三个测试的FF在很大程度上正确地捕获了Aβ肽与DMPC脂质双层的相互作用。这些差异不会抵消共识约束机制的特征。我们将我们的发现与其他FF评估进行了比较,并提出C22,C36和A14之间的协议是脂质双层中极性-非极性界面产生的有序排列效果的结果。通过将共有的Aβ结合机制与实验数据进行比较,我们推测三个测试的FF在很大程度上正确地捕获了Aβ肽与DMPC脂质双层的相互作用。
更新日期:2020-03-16
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