Center for the Study of Systems Biology, School of Biology, Georgia Institute of Technology, Atlanta, GA 30318, USA.
Proc Natl Acad Sci U S A. 2013 Jun 4;110(23):9344-9. doi: 10.1073/pnas.1300011110. Epub 2013 May 20.
The intrinsic ability of protein structures to exhibit the geometric and sequence properties required for ligand binding without evolutionary selection is shown by the coincidence of the properties of pockets in native, single domain proteins with those in computationally generated, compact homopolypeptide, artificial (ART) structures. The library of native pockets is covered by a remarkably small number of representative pockets (∼400), with virtually every native pocket having a statistically significant match in the ART library, suggesting that the library is complete. When sequences are selected for ART structures based on fold stability, pocket sequence conservation is coincident to native. The fact that structurally and sequentially similar pockets occur across fold classes combined with the small number of representative pockets in native proteins implies that promiscuous interactions are inherent to proteins. Based on comparison of PDB (real, single domain protein structures found in the Protein Data Bank) and ART structures and pockets, the widespread assumption that the co-occurrence of global structure, pocket similarity, and amino acid conservation demands an evolutionary relationship between proteins is shown to significantly underestimate the random background probability. Indeed, many features of biochemical function arise from the physical properties of proteins that evolution likely fine-tunes to achieve specificity. Finally, our study suggests that a repertoire of thermodynamically (marginally) stable proteins could engage in many of the biochemical reactions needed for living systems without selection for function, a conclusion with significant implications for the origin of life.
蛋白质结构具有展现配体结合所需的几何和序列特性的内在能力，这一点可以通过天然单域蛋白质口袋的特性与计算生成的、紧凑的均聚物、人工 (ART) 结构的特性相吻合得到证明。天然口袋的库由数量非常少的代表性口袋（约 400 个）覆盖，几乎每个天然口袋在 ART 库中都有统计学意义上的匹配，这表明该库是完整的。当根据折叠稳定性选择 ART 结构的序列时，口袋序列的保守性与天然序列一致。事实上，结构和序列相似的口袋在折叠类别中都存在，加上天然蛋白质中代表性口袋的数量很少，这意味着混杂相互作用是蛋白质固有的。通过比较 PDB（蛋白质数据库中的真实、单域蛋白质结构）和 ART 结构和口袋，广泛存在的假设是，全局结构、口袋相似性和氨基酸保守性的共同出现要求蛋白质之间存在进化关系，这表明这种假设显著低估了随机背景概率。事实上，生物化学功能的许多特征都源于蛋白质的物理特性，进化可能会对这些特性进行微调以实现特异性。最后，我们的研究表明，一组热力学（略有）稳定的蛋白质可以在没有功能选择的情况下参与生命系统所需的许多生化反应，这一结论对生命的起源具有重要意义。
