Experimental studies have reported that the amyloid-β proteins can form pores in cell membranes, and this could be one possible source of toxicity in Alzheimer's disease. Dissociation of these pores could therefore be a potential therapeutic approach. It is known that high photon density free-electron laser experiments and laser-induced nonequilibrium molecular dynamics simulations (NEMD) can dissociate amyloid fibrils at specific frequencies in vitro. Our question is whether NEMD simulations can dissociate amyloid pores in a bilayer mimicking a neuronal membrane, and as an example, we select a tetrameric Aβ42 β-barrel. Our simulations shows that the resonance between the laser field and the amide I vibrational mode of the barrel destabilises all intramolecular and intermolecular hydrogen bonds of Aβ42 and converts the β-barrel to a random/coil disordered oligomer. Starting from this disordered oligomer, extensive standard MD simulations shows sampling of disordered Aβ42 states without any increase of β-sheet and reports that the orientational order of lipids is minimally disturbed. Interestingly, the frequency to be employed to dissociate this beta-barrel is specific to the amino acid sequence. Taken together with our previous simulation results, this study indicates that infrared laser irradiation can dissociate amyloid fibrils and oligomers in bulk solution and in a membrane environment without affecting the surrounding molecules, offering therefore a promising way to retard the progression of AD.

实验研究报告称，淀粉样蛋白-β蛋白可以在细胞膜上形成孔，这可能是阿尔茨海默病的毒性来源之一。因此，这些孔的分离可能是一种潜在的治疗方法。众所周知，高光子密度自由电子激光实验和激光诱导的非平衡分子动力学模拟 (NEMD) 可以在体外以特定频率解离淀粉样原纤维。我们的问题是 NEMD 模拟是否可以在模拟神经元膜的双层中分离淀粉样蛋白孔，例如，我们选择四聚体 A β 42 β-桶。我们的模拟表明，激光场与桶的酰胺 I 振动模式之间的共振使 A β 42 的所有分子内和分子间氢键不稳定，并将β桶转化为无规/螺旋无序低聚物。从这种无序的低聚物开始，广泛的标准 MD 模拟显示了无序 A β 42 状态的采样，而没有任何β增加-sheet 并报告说脂质的取向顺序受到最小程度的干扰。有趣的是，用于解离这个β-桶的频率是特定于氨基酸序列的。结合我们之前的模拟结果，这项研究表明，红外激光照射可以解离大量溶液和膜环境中的淀粉样蛋白原纤维和低聚物，而不影响周围的分子，因此提供了一种延缓 AD 进展的有希望的方法。