Quantum chemical molecular dynamics and metadynamics simulation of aluminium binding to amyloid-ß and related peptides.
Quantum chemical molecular dynamics and metadynamics simulation of aluminium binding to amyloid-ß and related peptides.
复制标题
铝与淀粉样蛋白和相关肽结合的量子化学分子动力学和元动力学模拟。
DOI：
10.1098/rsos.191562
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发表时间：
2020
影响因子：
3.5
通讯作者：
Platts JA
中科院分区：
文献类型：
--
作者：
Platts JA
我们报告半经验紧结合模拟Al（III）和生物相关肽之间的相互作用。的GFN 2-XTB方法被证明是准确地再现先前报道的和密度泛函理论（DFT）计算的模型系统的几何形状。基于这种方法的分子动力学模拟能够在长达纳秒的时间尺度上对肽的灵活性进行采样，但这些时间尺度不足以探索金属-肽结合模式的潜在变化。为了实现这一点，使用均方根偏差作为集体变量的元自适应模拟。通过适当选择的偏置电位，这些能够有效地探索不同的配位模式，例如，通过模型肽中的Glu和/或Asp残基。使用这些方法，我们发现Al（III）与淀粉样蛋白-β的N-末端序列的结合是高度流动的，所有酸性侧链和几个主链氧参与配位。我们还表明，这样的模拟可以提供一种手段来predicta prioritespossible绑定模式作为一个更长的，原子模拟的先驱。
We report semi-empirical tight-binding simulations of the interaction between Al(III) and biologically relevant peptides. The GFN2-XTB method is shown to accurately reproduce previously reported and density functional theory (DFT)-calculated geometries of model systems. Molecular dynamics simulations based on this method are able to sample peptide flexibility over timescales of up to nanoseconds, but these timescales are insufficient to explore potential changes in metal–peptide binding modes. To achieve this, metadynamics simulations using root mean square deviation as a collective variable were employed. With suitably chosen biasing potentials, these are able to efficiently explore diverse coordination modes, for instance, through Glu and/or Asp residues in a model peptide. Using these methods, we find that Al(III) binding to the N-terminal sequence of amyloid-β is highly fluxional, with all acidic sidechains and several backbone oxygens participating in coordination. We also show that such simulations could provide a means to predicta prioripossible binding modes as a precursor to longer, atomistic simulations.