Department of Chemical and Biomolecular Engineering, University of Akron, Akron, Ohio 44325, USA.
Phys Chem Chem Phys. 2011 Sep 7;13(33):15200-10. doi: 10.1039/c1cp21156k. Epub 2011 Jul 19.
The misfolding and aggregation of β-amyloid peptides (Aβ) into amyloid fibrils, a process that has been pathologically linked to the onset of Alzheimer's disease, is dependent on the presence of a heterogeneous surface (e.g., cell membrane). Understanding of the kinetics of amyloid fibril formation and associated structural transition from monomers to intermediates and eventually to fibrils is critical for the development of viable therapeutic agents. In this work, using circular dichroism (CD), atomic force microscopy (AFM), surface plasmon resonance (SPR), and molecular dynamics (MD) simulations, we studied the adsorption, aggregation, and conformational changes of Aβ(1-42) from fresh monomers to fully grown fibrils on four model self-assembled monolayers (SAMs): hydrophobic CH(3)-terminated SAM, hydrophilic OH-terminated SAM, negatively charged COOH-terminated SAMs, and positively charged NH(2)-terminated SAM. The seeding effect of Aβ(1-42) on the kinetics of Aβ aggregation on different SAMs is also examined. The CD, AFM, and SPR data show that all of these SAMs greatly accelerate the formation of β-sheets and amyloid fibrils through surface-enhanced interactions, but Aβ(1-42) peptides preferentially adsorb on a hydrophobic CH(3)-SAM and a positively charged NH(2)-SAM with much stronger interactions than on a hydrophilic OH-SAM and a negatively charged COOH-SAM. MD simulations further reveal that hydrophobic interactions present a general driving force for Aβ adsorption on all SAMs. As Aβ aggregates grow into larger species by packing hydrophobic C-terminals to form a hydrophobic core while exposing hydrophilic and negatively charged N-terminals to solution, electrostatic interactions become more strengthened when they interact with the SAMs especially for the COOH-SAM and the NH(2)-SAM. Thus, both hydrophobic and electrostatic interactions contribute differently to different Aβ-SAM systems and to different aggregation stages. A postulated mechanism is proposed to describe the structure and kinetics of Aβ aggregation from aqueous solution to the SAMs, providing valuable insights into Aβ aggregation on biological cell membranes.
β-淀粉样肽（Aβ）错误折叠和聚集形成淀粉样纤维，这一过程与阿尔茨海默病的发病机制密切相关，依赖于异质表面（例如细胞膜）的存在。了解淀粉样纤维形成的动力学以及与之相关的结构转变，从单体到中间体，最终到纤维，对于开发可行的治疗药物至关重要。在这项工作中，我们使用圆二色性（CD）、原子力显微镜（AFM）、表面等离子体共振（SPR）和分子动力学（MD）模拟研究了 Aβ（1-42）从新鲜单体到完全生长的纤维在四种模型自组装单层（SAM）上的吸附、聚集和构象变化：疏水 CH（3）-端 SAM、亲水 OH-端 SAM、带负电的 COOH-端 SAMs 和带正电的 NH（2）-端 SAM。还研究了 Aβ（1-42）在不同 SAM 上对 Aβ 聚集动力学的成核效应。CD、AFM 和 SPR 数据表明，所有这些 SAM 都通过表面增强相互作用极大地加速了β-折叠和淀粉样纤维的形成，但 Aβ（1-42）肽优先吸附在疏水性 CH（3）-SAM 和带正电的 NH（2）-SAM 上，与亲水性 OH-SAM 和带负电的 COOH-SAM 相比，相互作用更强。MD 模拟进一步表明，疏水性相互作用是 Aβ 在所有 SAM 上吸附的一般驱动力。随着 Aβ 聚集体通过包装疏水性 C 末端形成疏水性核心，同时将亲水性和带负电的 N 末端暴露在溶液中而生长成更大的物种，静电相互作用在与 SAM 相互作用时变得更强，尤其是对于 COOH-SAM 和 NH（2）-SAM。因此，疏水性和静电相互作用对不同的 Aβ-SAM 系统和不同的聚集阶段有不同的贡献。提出了一种假设的机制来描述 Aβ 从水溶液到 SAM 的聚集结构和动力学，为 Aβ 在生物细胞膜上的聚集提供了有价值的见解。
