Groningen Biomolecular Sciences and Biotechnology Institute and Zernike Institute for Advanced Materials, University of Groningen , Groningen 9747 AG, The Netherlands.
Laboratory of Chemical Biology and Signal Transduction, The Rockefeller University , 1230 York Avenue, New York, New York 10065, United States.
J Phys Chem B. 2018 Jan 25;122(3):1081-1091. doi: 10.1021/acs.jpcb.7b10233. Epub 2018 Jan 5.
Amyloid fibrils are highly ordered protein aggregates associated with more than 40 human diseases. The exact conditions under which the fibrils are grown determine many types of reported fibril polymorphism, including different twist patterns. Twist-based polymorphs display unique mechanical properties in vitro, and the relevance of twist polymorphism in amyloid diseases has been suggested. We present transmission electron microscopy images of Aβ42-derived (amyloid β) fibrils, which are associated with Alzheimer's disease, demonstrating the presence of twist variability even within a single long fibril. To better understand the molecular underpinnings of twist polymorphism, we present a structural and thermodynamics analysis of molecular dynamics simulations of the twisting of β-sheet protofilaments of a well-characterized cross-β model: the GNNQQNY peptide from the yeast prion Sup35. The results show that a protofilament model of GNNQQNY is able to adopt twist angles from -11° on the left-hand side to +8° on the right-hand side in response to various external conditions, keeping an unchanged peptide structure. The potential of mean force (PMF) of this cross-β structure upon twisting revealed that only ∼2kT per peptide are needed to stabilize a straight conformation with respect to the left-handed free-energy minimum. The PMF also shows that the canonical structural core of β-sheets, i.e., the hydrogen-bonded backbone β-strands, favors the straight conformation. However, the concerted effects of the side chains contribute to twisting, which provides a rationale to correlate polypeptide sequence, environmental growth conditions and number of protofilaments in a fibril with twist polymorphisms.
淀粉样纤维是与超过 40 种人类疾病相关的高度有序的蛋白质聚集体。纤维生长的确切条件决定了许多报道的纤维多态性类型，包括不同的扭曲模式。基于扭曲的多态性在体外表现出独特的机械性能，并且在淀粉样疾病中已经提出了扭曲多态性的相关性。我们展示了与阿尔茨海默病相关的 Aβ42 衍生（淀粉样 β）纤维的透射电子显微镜图像，这些纤维甚至在单个长纤维内显示出扭曲变化。为了更好地理解扭曲多态性的分子基础，我们对扭曲β-片层原纤维的分子动力学模拟进行了结构和热力学分析：酵母朊病毒 Sup35 的 GNNQQNY 肽。结果表明，GNNQQNY 的原纤维模型能够在各种外部条件下从左手的-11°转变为右手的+8°，保持不变的肽结构。扭曲对这种交叉-β结构的平均势能（PMF）表明，每个肽只需要约 2kT 即可稳定与左手自由能最小值相对的直线构象。PMF 还表明，β-片层的典型结构核心，即氢键连接的骨架β-链，有利于直线构象。然而，侧链的协同效应有助于扭曲，这为多肽序列、环境生长条件和纤维中的原纤维数量与扭曲多态性相关提供了依据。
