Department of Chemistry and Biochemistry, Physical Science Building 356, University of California Santa Cruz, 1156 High Street, Santa Cruz, CA, 95064, USA.
Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, 90095, USA.
Sci Rep. 2017 Oct 2;7(1):12433. doi: 10.1038/s41598-017-10525-5.
Intrinsically disordered protein (IDP) conformers occupy large regions of conformational space and display relatively flat energy surfaces. Amyloid-forming IDPs, unlike natively folded proteins, have folding trajectories that frequently involve movements up shallow energy gradients prior to the "downhill" folding leading to fibril formation. We suggest that structural perturbations caused by chiral inversions of amino acid side-chains may be especially valuable in elucidating these pathways of IDP folding. Chiral inversions are subtle in that they do not change side-chain size, flexibility, hydropathy, charge, or polarizability. They allow focus to be placed solely on the question of how changes in amino acid side-chain orientation, and the resultant alterations in peptide backbone structure, affect a peptide's conformational landscape (Ramachandran space). If specific inversions affect folding and assembly, then the sites involved likely are important in mediating these processes. We suggest here a "focused chiral mutant library" approach for the unbiased study of amyloid-forming IDPs.
无规蛋白构象（IDP）构象占据了构象空间的大片区域，并显示出相对平坦的能量表面。与天然折叠的蛋白质不同，淀粉样形成 IDP 的折叠轨迹经常涉及在“下坡”折叠导致纤维形成之前沿浅能梯度的运动。我们认为，由氨基酸侧链的手性反转引起的结构扰动可能特别有助于阐明这些 IDP 折叠途径。手性反转很细微，因为它们不会改变侧链大小、灵活性、疏水性、电荷或极化率。它们可以将注意力完全集中在氨基酸侧链取向的变化以及肽骨架结构的变化如何影响肽的构象景观（Ramachandran 空间）的问题上。如果特定的反转影响折叠和组装，那么涉及的部位可能在介导这些过程中很重要。我们在这里提出了一种“聚焦手性突变体文库”方法，用于无偏研究淀粉样形成 IDP。
