Department of Applied Physics, Nagoya University, Nagoya 464-8601, Japan.
Department of Complex Systems Science, Nagoya University, Nagoya 464-8601, Japan.
Molecules. 2022 May 31;27(11):3547. doi: 10.3390/molecules27113547.
Superfolds are folds commonly observed among evolutionarily unrelated multiple superfamilies of proteins. Since discovering superfolds almost two decades ago, structural rules distinguishing superfolds from the other ordinary folds have been explored but remained elusive. Here, we analyzed a typical superfold, the ferredoxin fold, and the fold which reverses the N to C terminus direction from the ferredoxin fold as a case study to find the rule to distinguish superfolds from the other folds. Though all the known structural characteristics for superfolds apply to both the ferredoxin fold and the reverse ferredoxin fold, the reverse fold has been found only in a single superfamily. The database analyses in the present study revealed the structural preferences of αβ- and βα-units; the preferences separate two α-helices in the ferredoxin fold, preventing their collision and stabilizing the fold. In contrast, in the reverse ferredoxin fold, the preferences bring two helices near each other, inducing structural conflict. The Rosetta folding simulations suggested that the ferredoxin fold is physically much more realizable than the reverse ferredoxin fold. Therefore, we propose that minimal structural conflict or minimal frustration among secondary structures is the rule to distinguish a superfold from ordinary folds. Intriguingly, the database analyses revealed that a most stringent structural rule in proteins, the right-handedness of the βαβ-unit, is broken in a set of structures to prevent the frustration, suggesting the proposed rule of minimum frustration among secondary structural units is comparably strong as the right-handedness rule of the βαβ-unit.
超折叠是在进化上不相关的多个蛋白质超家族中常见的折叠。自从近二十年前发现超折叠以来，已经探索了区分超折叠与其他普通折叠的结构规则，但仍然难以捉摸。在这里，我们分析了一个典型的超折叠结构，即铁氧还蛋白折叠，以及从铁氧还蛋白折叠中反向 N 到 C 端的折叠，作为一个案例研究，以找到区分超折叠与其他折叠的规则。尽管所有已知的超折叠结构特征都适用于铁氧还蛋白折叠和反向铁氧还蛋白折叠，但反向折叠仅在单个超家族中发现。本研究的数据库分析揭示了 αβ-和 βα-单元的结构偏好；这些偏好将铁氧还蛋白折叠中的两个α-螺旋分开，防止它们发生碰撞并稳定折叠。相比之下，在反向铁氧还蛋白折叠中，偏好将两个螺旋相互靠近，导致结构冲突。罗塞塔折叠模拟表明，铁氧还蛋白折叠在物理上比反向铁氧还蛋白折叠更容易实现。因此，我们提出最小的结构冲突或二级结构之间的最小挫折是区分超折叠与普通折叠的规则。有趣的是，数据库分析揭示了蛋白质中最严格的结构规则之一，即 βαβ-单元的右手性，在一组结构中被打破，以防止挫折，这表明所提出的最小二级结构单元之间的挫折规则与 βαβ-单元的右手性规则一样强大。
