Mutter Shaun T, Turner Matthew, Deeth Robert J, Platts James A
School of Chemistry, Cardiff University, Park Place, Cardiff, CF10 3AT, UK.
Department of Chemistry, University of Warwick, Gibbet Hill, Coventry, CV4 7AL, UK.
Heliyon. 2019 Dec 31;6(1):e03071. doi: 10.1016/j.heliyon.2019.e03071. eCollection 2020 Jan.
We report microsecond timescale ligand field molecular dynamics simulations of the copper complexes of three known mutants of the amyloid-β peptide, E22G, E22Q and E22K, alongside the naturally occurring sequence. We find that all three mutants lead to formation of less compact structures than the wild-type: E22Q is the most similar to the native peptide, while E22G and especially E22K are markedly different in size, shape and stability. Turn and coil structures dominate all structures studied but subtle differences in helical and β-sheet distribution are noted, especially in the C-terminal region. The origin of these changes is traced to disruption of key salt bridges: in particular, the Asp23-Lys28 bridge that is prevalent in the wild-type is absent in E22G and E22K, while Lys22 in the latter mutant forms a strong association with Asp23. We surmise that the drastically different pattern of salt bridges in the mutants lead to adoption of a different structural ensemble of the peptide backbone, and speculate that this might affect the ability of the mutant peptides to aggregate in the same manner as known for the wild-type.
我们报告了对淀粉样β肽的三种已知突变体E22G、E22Q和E22K以及天然序列的铜配合物进行的微秒级配体场分子动力学模拟。我们发现，与野生型相比，所有这三种突变体都会导致形成不太紧凑的结构：E22Q与天然肽最相似，而E22G尤其是E22K在大小、形状和稳定性方面有明显差异。转角和卷曲结构在所有研究的结构中占主导地位，但注意到螺旋和β折叠分布存在细微差异，尤其是在C端区域。这些变化的根源可追溯到关键盐桥的破坏：特别是，野生型中普遍存在的Asp23-Lys28桥在E22G和E22K中不存在，而后一种突变体中的Lys22与Asp23形成了强关联。我们推测，突变体中截然不同的盐桥模式导致肽主链采用不同的结构集合，并推测这可能会影响突变肽以与野生型已知方式相同的方式聚集的能力。
