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首页> 外文期刊>The journal of physical chemistry, B. Condensed matter, materials, surfaces, interfaces & biophysical >Changes to the Structure and Dynamics in Mutations of Aβ_(21-30) Caused by Ions in Solution
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Changes to the Structure and Dynamics in Mutations of Aβ_(21-30) Caused by Ions in Solution

机译：溶液中离子引起的Aβ_（21-30）突变的结构和动力学变化

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摘要

The structure and dynamics of the 21-30 fragment of the amyloid β-protein (Aβ_(21-30)) and its Dutch [Glu22GIn], Arctic [Glu22Gly], and Iowa [Asp23Asn] isoforms are of considerable importance, as their folding may play an important role in the pathogenesis of sporadic and familial forms of Alzheimer's disease and cerebral amyloid angiopathy. A full understanding of this pathologic folding in in vivo environments is still elusive. Here we examine the interactions and effects of two neurobiologically relevant salts (CaCl2 and KC1) on the structure and dynamics of Aβ_(21-30) decapeptide monomers containing the Dutch, Arctic, and Iowa charge-modifying point mutations using isobaric—isothermal (NPT) explicit water all-atom molecular-dynamics simulations. Measurements of secondary structure populations, intrapeptide hydrogen bonding, salt bridging, secondary structure lifetimes, cation—residue contacts, water— peptide hydrogen bonding, and hydration-shell water residence times reveal a variety of ion and mutation-dependent modifications to the decapeptide's structure and dynamics. In general, Ca~(2+) has the effect of increasing coil-state populations and lifetimes, modifying the behavior of the decapeptide's hydration shell and diminishing intrapeptide hydrogen bonding, while K~+ is found to diminish coil populations and lifetimes and, for the case of the Iowa mutant, dramatically increase the decapeptide's propensity for β secondary structures. Mutation-dependent effects highlight the different roles of the Glu22 and Asp23 residues in either solvating or enhancing turn structures, respectively. Taken together, our results provide insights into the differential roles of different ionic species as well as specific effects on the Glu22 and Asp23 residues of Aβ_(21-30) mediated by ion— decapeptide interactions and the solvent, which could be important interaction mechanisms relevant to the peptide's behavior in both in vitro and in vivo environments.
机译：淀粉样β蛋白（Aβ_（21-30））的21-30片段及其荷兰语[Glu22GIn]，北极[Glu22Gly]和爱荷华州[Asp23Asn]同工型的结构和动力学非常重要，因为它们可以折叠可能在偶发性和家族性阿尔茨海默氏病和脑淀粉样血管病的发病机理中起重要作用。在体内环境中对这种病理学折叠的全面了解仍然难以捉摸。在这里，我们使用等压-等温（NPT）方法研究了两种神经生物学相关盐（CaCl2和KC1）对包含Dutch，北极和爱荷华州荷电修饰点突变的Aβ_（21-30）十肽单体的结构和动力学的相互作用和影响。 ）明确的水全原子分子动力学模拟。测量二级结构种群，内肽氢键，盐桥键，二级结构寿命，阳离子-残基接触，水-肽氢键和水合壳水停留时间揭示了十肽结构的各种离子和依赖突变的修饰和动力学。通常，Ca〜（2+）具有增加线圈态种群和寿命，改变十肽水合壳行为和减少内部肽氢键的作用，而K〜+则可以减少线圈种群和寿命，并且，在爱荷华州突变体的情况下，大大增加了十肽对β二级结构的倾向。突变依赖性效应突出了Glu22和Asp23残基分别在溶剂化或增强转弯结构中的不同作用。综上所述，我们的结果提供了洞察不同离子种类的不同作用以及离子-十肽相互作用和溶剂介导的对Aβ_（21-30）的Glu22和Asp23残基的特定作用的重要原因，这可能是相关的重要相互作用机制肽在体外和体内环境中的行为。

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