Lockhart Christopher, Klimov Dmitri K
School of Systems Biology, George Mason University , Manassas, Virginia 20110, United States.
J Chem Inf Model. 2017 Oct 23;57(10):2554-2565. doi: 10.1021/acs.jcim.7b00431. Epub 2017 Oct 2.
Using isobaric-isothermal all-atom replica-exchange molecular dynamics (REMD) simulations, we investigated the equilibrium binding of Aβ10-40 monomers to the zwitterionic dimyristoylphosphatidylcholine (DMPC) bilayer containing cholesterol. Our previous REMD simulations, which studied binding of the same peptide to the cholesterol-free DMPC bilayer, served as a control, against which we measured the impact of cholesterol. Our findings are as follows. First, addition of cholesterol to the DMPC bilayer partially expels the Aβ peptide from the hydrophobic core and promotes its binding to bilayer polar headgroups. Using thermodynamic and energetics analyses, we argued that Aβ partial expulsion is not related to cholesterol-induced changes in lateral pressure within the bilayer but is caused by binding energetics, which favors Aβ binding to the surface of the densely packed cholesterol-rich bilayer. Second, cholesterol has a protective effect on the DMPC bilayer structure against perturbations caused by Aβ binding. More specifically, cholesterol reduces bilayer thinning and overall depletion of bilayer density beneath the Aβ binding footprint. Third, we found that the Aβ peptide contains a single cholesterol binding site, which involves hydrophobic C-terminal amino acids (Ile31-Val36), Phe19, and Phe20 from the central hydrophobic cluster, and cationic Lys28 from the turn region. This binding site accounts for about 76% of all Aβ-cholesterol interactions. Because cholesterol binding site in the Aβ10-40 peptide does not contain the GXXXG motif featured in cholesterol interactions with the transmembrane domain C99 of the β-amyloid precursor protein, we argued that the binding mechanisms for Aβ and C99 are distinct reflecting their different conformations and positions in the lipid bilayer. Fourth, cholesterol sharply reduces the helical propensity in the bound Aβ peptide. As a result, cholesterol largely eliminates the emergence of helical structure observed upon Aβ transition from a water environment to the cholesterol-free DMPC bilayer. We explain this effect by the formation of hydrogen bonds between cholesterol and the Aβ backbone, which prevent helix formation. Taken together, we expect that our simulations will advance understanding of a molecular-level mechanism behind the role of cholesterol in Alzheimer's disease.
我们使用等压等温全原子副本交换分子动力学（REMD）模拟，研究了Aβ10 - 40单体与含有胆固醇的两性离子二肉豆蔻酰磷脂酰胆碱（DMPC）双层膜的平衡结合。我们之前的REMD模拟研究了同一肽与不含胆固醇的DMPC双层膜的结合，作为对照，以此来衡量胆固醇的影响。我们的研究结果如下。首先，向DMPC双层膜中添加胆固醇会使Aβ肽部分从疏水核心排出，并促进其与双层膜极性头部基团的结合。通过热力学和能量学分析，我们认为Aβ的部分排出与胆固醇引起的双层膜内横向压力变化无关，而是由结合能引起的，这有利于Aβ与紧密堆积的富含胆固醇的双层膜表面结合。其次，胆固醇对DMPC双层膜结构具有保护作用，可抵御由Aβ结合引起的扰动。更具体地说，胆固醇减少了双层膜变薄以及Aβ结合足迹下方双层膜密度的整体降低。第三，我们发现Aβ肽含有一个单一的胆固醇结合位点，该位点涉及来自中央疏水簇的疏水C端氨基酸（Ile31 - Val36）、Phe19和Phe20，以及来自转折区域的阳离子Lys28。这个结合位点占所有Aβ - 胆固醇相互作用的约76%。由于Aβ10 - 40肽中的胆固醇结合位点不包含β - 淀粉样前体蛋白跨膜结构域C99与胆固醇相互作用中特有的GXXXG基序，我们认为Aβ和C99的结合机制不同，这反映了它们在脂质双层中的不同构象和位置。第四，胆固醇显著降低了结合的Aβ肽中的螺旋倾向。因此，胆固醇在很大程度上消除了Aβ从水环境转变为不含胆固醇的DMPC双层膜时观察到的螺旋结构的出现。我们通过胆固醇与Aβ主链之间形成氢键来解释这种效应，这阻止了螺旋的形成。综上所述，我们期望我们的模拟将推进对胆固醇在阿尔茨海默病中作用背后分子水平机制的理解。
