Nagy-Smith Katelyn, Moore Eric, Schneider Joel, Tycko Robert
Chemical Biology Laboratory, Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, MD 21702; Department of Chemistry and Biochemistry, University of Delaware, Newark, DE 19716;
Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892-0520.
Proc Natl Acad Sci U S A. 2015 Aug 11;112(32):9816-21. doi: 10.1073/pnas.1509313112. Epub 2015 Jul 27.
Most, if not all, peptide- and protein-based hydrogels formed by self-assembly can be characterized as kinetically trapped 3D networks of fibrils. The propensity of disease-associated amyloid-forming peptides and proteins to assemble into polymorphic fibrils suggests that cross-β fibrils comprising hydrogels may also be polymorphic. We use solid-state NMR to determine the molecular and supramolecular structure of MAX1, a de novo designed gel-forming peptide, in its fibrillar state. We find that MAX1 adopts a β-hairpin conformation and self-assembles with high fidelity into a double-layered cross-β structure. Hairpins assemble with an in-register Syn orientation within each β-sheet layer and with an Anti orientation between layers. Surprisingly, although the MAX1 fibril network is kinetically trapped, solid-state NMR data show that fibrils within this network are monomorphic and most likely represent the thermodynamic ground state. Intermolecular interactions not available in alternative structural arrangements apparently dictate this monomorphic behavior.
大多数（如果不是全部的话）通过自组装形成的基于肽和蛋白质的水凝胶都可被表征为动力学捕获的原纤维三维网络。与疾病相关的形成淀粉样蛋白的肽和蛋白质组装成多态性原纤维的倾向表明，构成水凝胶的交叉β原纤维也可能是多态性的。我们使用固态核磁共振来确定一种从头设计的凝胶形成肽MAX1在其纤维状态下的分子和超分子结构。我们发现MAX1采用β-发夹构象，并以高保真度自组装成双层交叉β结构。发夹在每个β-折叠层内以对齐的Syn方向组装，而在层间以反方向组装。令人惊讶的是，尽管MAX1纤维网络是动力学捕获的，但固态核磁共振数据表明，该网络内的纤维是单态的，很可能代表热力学基态。替代结构排列中不存在的分子间相互作用显然决定了这种单态行为。
