Laboratory of Biophysics, Institute for Advanced Study in Technology, Ton Duc Thang University, Ho Chi Minh City 72915, Vietnam.
Faculty of Pharmacy, Ton Duc Thang University, Ho Chi Minh City 72915, Vietnam.
J Chem Inf Model. 2023 Jul 24;63(14):4376-4382. doi: 10.1021/acs.jcim.3c00706. Epub 2023 Jul 6.
The folding/misfolding of membrane-permiable Amyloid beta (Aβ) peptides is likely associated with the advancing stage of Alzheimer's disease (AD) by disrupting Ca homeostasis. In this context, the aggregation of four transmembrane Aβ peptides was investigated using temperature replica-exchange molecular dynamics (REMD) simulations. The obtained results indicated that the secondary structure of transmembrane Aβ peptides tends to have different propensities compared to those in solution. Interestingly, the residues favorably forming β-structure were interleaved by residues rigidly adopting turn-structure. A combination of β and turn regions likely forms a pore structure. Six morphologies of 4Aβ were found over the free energy landscape and clustering analyses. Among these, the morphologies include (1) Aβ binding onto the membrane surface and three transmembrane Aβ; (2) three helical and coil transmembrane Aβ; (3) four helical transmembrane Aβ; (4) three helical and one β-hairpin transmembrane Aβ; (5) two helical and two β-strand transmembrane Aβ; and (6) three β-strand and one helical transmembrane Aβ. Although the formation of the β-barrel structure was not observed during the 0.28 ms─long MD simulation, the structure is likely to form when the simulation time is further extended.
跨膜淀粉样β（Aβ）肽的折叠/错误折叠可能通过破坏钙稳态与阿尔茨海默病（AD）的进展阶段有关。在这种情况下，使用温度复制交换分子动力学（REMD）模拟研究了四个跨膜 Aβ 肽的聚集。结果表明，跨膜 Aβ 肽的二级结构与溶液中的结构相比具有不同的倾向。有趣的是，有利于形成β结构的残基被刚性采用转角结构的残基交错。β 结构和转角区域的组合可能形成孔结构。在自由能景观和聚类分析中发现了 4Aβ 的六种形态。其中包括（1）Aβ 结合到膜表面和三个跨膜 Aβ；（2）三个螺旋和线圈跨膜 Aβ；（3）四个螺旋跨膜 Aβ；（4）三个螺旋和一个β发夹跨膜 Aβ；（5）两个螺旋和两个β-链跨膜 Aβ；和（6）三个β-链和一个螺旋跨膜 Aβ。尽管在 0.28 毫秒长的 MD 模拟过程中没有观察到β-桶结构的形成，但当进一步延长模拟时间时，该结构可能会形成。
