Center for the Study of Systems Biology, Georgia Institute of Technology, 250 14th St NW, Atlanta, GA 30076, USA.
Phys Chem Chem Phys. 2011 Oct 14;13(38):17044-55. doi: 10.1039/c1cp21140d. Epub 2011 Jun 8.
The intrinsic ability of protein structures to exhibit the geometric features required for molecular function in the absence of evolution is examined in the context of three systems: the reference set of real, single domain protein structures, a library of computationally generated, compact homopolypeptides, artificial structures with protein-like secondary structural elements, and quasi-spherical random proteins packed at the same density as proteins but lacking backbone secondary structure and hydrogen bonding. Without any evolutionary selection, the library of artificial structures has similar backbone hydrogen bonding, global shape, surface to volume ratio and statistically significant structural matches to real protein global structures. Moreover, these artificial structures have native like ligand binding cavities, and a tiny subset has interfacial geometries consistent with native-like protein-protein interactions and DNA binding. In contrast, the quasi-spherical random proteins, being devoid of secondary structure, have a lower surface to volume ratio and lack ligand binding pockets and intermolecular interaction interfaces. Surprisingly, these quasi-spherical random proteins exhibit protein like distributions of virtual bond angles and almost all have a statistically significant structural match to real protein structures. This implies that it is local chain stiffness, even without backbone hydrogen bonding, and compactness that give rise to the likely completeness of the library solved single domain protein structures. These studies also suggest that the packing of secondary structural elements generates the requisite geometry for intermolecular binding. Thus, backbone hydrogen bonding plays an important role not only in protein structure but also in protein function. Such ability to bind biological molecules is an inherent feature of protein structure; if combined with appropriate protein sequences, it could provide the non-zero background probability for low-level function that evolution requires for selection to occur.
蛋白质结构在没有进化的情况下表现出分子功能所需的几何特征的内在能力，在以下三个系统中进行了考察：真实的单域蛋白质结构参考集、计算生成的紧凑同聚多肽文库、具有类似蛋白质二级结构元件的人工结构以及与蛋白质具有相同密度但缺乏骨架二级结构和氢键的拟球状无规蛋白质。在没有任何进化选择的情况下，人工结构文库具有相似的骨架氢键、整体形状、表面积与体积比以及与真实蛋白质整体结构具有统计学意义的结构匹配。此外，这些人工结构具有类似天然配体结合腔，并且一小部分具有与天然类似的蛋白质-蛋白质相互作用和 DNA 结合的界面几何形状。相比之下，缺乏二级结构的拟球状无规蛋白质具有较低的表面积与体积比，并且缺乏配体结合口袋和分子间相互作用界面。令人惊讶的是，这些拟球状无规蛋白质表现出类似蛋白质的虚拟键角分布，并且几乎所有的蛋白质都与真实蛋白质结构具有统计学意义的结构匹配。这意味着正是局部链刚性，即使没有骨架氢键，以及紧凑性导致了文库中解决的单域蛋白质结构的完整性。这些研究还表明，二级结构元件的组装生成了分子间结合所需的几何形状。因此，骨架氢键不仅在蛋白质结构中而且在蛋白质功能中都起着重要作用。这种结合生物分子的能力是蛋白质结构的固有特征；如果与适当的蛋白质序列结合，它可以为进化所需的选择发生提供低水平功能的非零背景概率。
