Molecular Modeling Laboratory, Department of Chemistry, Indian Institute of Technology, Kharagpur 721302, India.
J Chem Phys. 2018 Aug 14;149(6):065101. doi: 10.1063/1.5040672.
Aggregation of amyloid beta (A) peptides in the brain is responsible for one of the most devastating neurodegenerative diseases, namely, Alzheimer's disease. In this study, we have carried out atomistic molecular dynamics simulations to explore the effects of non-uniform structural distortions of A pre-fibrillar aggregates of different sizes on the microscopic structure and ordering of water molecules confined within their amphiphilic nanocores. The calculations revealed non-uniform peptide-water interactions resulting in simultaneous existence of both highly ordered and disordered water molecules within the spatially heterogeneous confined environment of the protofilament cores. It is found that the high degree of ordering originates from a sizable fraction of doubly coordinated core water molecules, while the randomly oriented ones are those that are coordinated with three neighbors in their first coordination shells. Furthermore, it is quantitatively demonstrated that relative fractions of these two types of water molecules are correlated with the protofilament core topology and the degree of confinement within that. It is proposed that the ordered core waters are likely to stabilize the A protofilaments by screening the residue charges and favoring water-mediated salt bridge formations, while the randomly oriented ones can drive further growth of the protofilaments by being displaced easily during the docking of additional peptides. In that way, both types of core water molecules can play equally important roles in controlling the growth and stability of the A-aggregates.
淀粉样蛋白 β (A) 肽在大脑中的聚集是导致最具破坏性的神经退行性疾病之一，即阿尔茨海默病的原因之一。在这项研究中，我们进行了原子分子动力学模拟，以探索不同大小的 A 预纤维聚集物的非均匀结构变形对其亲水分子纳米核心内受限水分子的微观结构和有序性的影响。计算结果表明，非均匀的肽-水相互作用导致在原纤维核心的空间异质受限环境中同时存在高度有序和无序的水分子。研究发现，高度有序的起源于相当一部分双配位核心水分子，而那些在其第一配位壳中与三个相邻原子配位的水分子则是无序的。此外，定量证明了这两种类型的水分子的相对分数与原纤维核心拓扑结构及其受限程度有关。研究提出，有序的核心水分子可能通过屏蔽残基电荷来稳定 A 原纤维，并有利于水介导的盐桥形成，而随机取向的水分子可以通过在附加肽对接过程中容易被取代来促进原纤维的进一步生长。这样，这两种核心水分子都可以在控制 A 聚集物的生长和稳定性方面发挥同等重要的作用。
